TW548271B - Novel piperidine derivatives having an exocyclic double bond with analgesic effects - Google Patents

Abstract

Compounds of general formula (I) are disclosed and claimed in the present application, as well as their pharmaceutically acceptable salts, pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain.

Description

548271 A7

V. Description of the invention (1) The scope of the present invention is related to novel compounds, their manufacturing methods, their uses, and pharmaceutical compositions of this compound. Novel compounds are used for treatment, especially: new pain. Background of the invention Identified as having a role in many bodily functions such as the circulatory and pain systems. Therefore, β-receptor ligands have been found to be potentially useful as analgesics and / or antihypertensive agents. Β-receptor ligands have also been shown to be immunomodulatory Activity. The identification of at least 3 different sepal-like receptor groups (&quot;, 4 and 0) has now been confirmed, and all 3 are apparent in many species including the human central and peripheral nervous system. When When more than one of these receptors has been activated, analgesic effects have been observed in various animal models .: With very few exceptions, the currently available selective opioid &amp; ligands are peptides in nature and are not suitable by nature Systematic route of administration. Some non-peptide beta antagonists have been used for some time (see Dingakemori and porgoghese, 1 992, Ann · Rev · Pharmac01 Tex, 32; M, ·, summary) These compounds, For example, the binding of naltrindole to #receptor suffers a much poorer selectivity (i.e., <10 times) for β receptors, and there is no current analgesic activity. This fact strengthens the development of The need for highly selective non-peptide ligands. The problem in the present invention is to find new compounds with improved side effects and possible oral effects compared to the current #agonist, which has improved analgesic properties and possible oral effects. The analgesics that have been identified and exist in the prior art have many shortcomings, such as 548271 A7 — a _______B7 __ 5. Description of the invention (2), etc. suffer from poor pharmacokinetics and no analgesic effect when administered in a systematic way Moreover, the better compound has been documented and described in the prior art, which shows convulsive effects when administered systemically. The above problems have been solved by developing novel compounds of the hexahydropyridine ring with an extra-ring double bond (see below). And solve. Summary of the invention

The novel compounds according to the invention are defined by the general formula (1) A B

I r2 c: ⑴

In the formula N1, R1 is selected from printed by the Consumer Cooperative of the Central Bureau of Quasi-Staff of the Ministry of Economic Affairs, branched or linear C! -C6 alkyl, Ci-Cs alkenyl, C3-C8 cycloalkyl, C4_C8 (alkyl-cycloalkane Group), wherein the alkyl group is Cl-C2 alkyl group and the cycloalkyl group is C3-C6 cycloalkyl group; C6-C1G aryl group; or 5 to 10 members selected from any one of c, S, N and 0 Atom heteroaryl; where aryl and heteroaryl are optionally and independently selected from 1 or 2 selected from η, CH3,-(CH2) PCF3, halogen, -CONR5R4, -COOR5 &gt; .C0R5 n. ch2) pNR5R4 &gt;-(CH2) pCH3 (CH2) pSOR5R4 ^ (CH2) pS〇2R5 and _ (CH2) pS02NR5 substitution of any one of the substituents, the paper size applies the Chinese National Standard (CNS) A4 specifications (210X297 mm) _ ~ 5 ~ ______ 548271 A7 --____ Β7 ____ V. In the description of the invention (3), R4 and R5 are each as defined for Ri above, and ρ is 0, 1 or 2; (cvc2 base) -(C6_ClGaryl); or (Ci-c2alkyl) heteroaryl, having 5 to 10 heteroaryl moieties selected from any one of c, s, N and 0, and wherein the aryl or hetero The aryl group may be independently and independently selected from 1 or 2 from Η, CH 3 .- (CH2) qCF3, halogen, -CONR5R4, -COOR5, -COR5,-(CH2) qNR5R4 &gt;-(CH2) qCH3 (CH2) qSOR5R4 &gt;-(CH2) qS02R5 &gt;-(CH2) qS. 2NR5 and-(CH2) pOR5 are substituted with any substituent, wherein r4 and r5 are each independently as defined for r1 above, and q is 0, 1 or 2; and

In the formula, R18, R19, R20, R21, R22 ,, R24 &amp; r25 are each independently fluorene, K6 alkyl or Ci-C6 alkenyl; R2 and R3 are each independently H * C1-C6 alkyl; A is selected Self-adhesive paper_printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

548271 A7 B7 V. Description of the invention (4

In the formula, R8, R9, Ri0, Rn ,, R13, r14, r15, r16 and R17 are each independently as defined for Ri above, and wherein the phenyl ring of each A substituent may be independently and independently of the phenyl ring Any position is selected from 丨 or 2 respectively from Η, CH3, &lt; CH2) qCF3, ^ element, _c〇nr6r7, c〇〇6 〇r6,-(CH2) rNRV, _ (CH2) rCH3 (CH2) rSOR6,-(CH2) rS〇2R6 and _ (CH2) rS〇2NR6R7 are substituted by the substituents Z1 and Z2, each of which is independently as defined for R1 above, and r is 0, 1 or 2; Q is C5 C6 louse An aryl or heterohydrogen group has 5 or 6 atoms selected from c, s, N and 0; CyC6 cycloalkyl, or heterocycloalkyl has 5 or 6 selected from c, Ν, 0 and Any atom of S; and each Q in it may be replaced by the Z1 and Z2 substituents as defined above; printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-installed-(Please read the precautions on the back before filling this page ) Let B be a substituted or unsubstituted aromatic, heteroaromatic, hydrogenaromatic or heterohydroaromatic motif knife with 5 to 10 atoms selected from c, S, N and 0, as appropriate and Independently consists of 1 or 2 selected from H, ch3, _ (CH2) tCF3 Halogen, (CH2) tCONR5R4,-(CH2) tNR5R4,-(CH2) tCOR5,-(CH2) tCOOR5, OR5,-(CH2) tSOR5,-(CH2) tS〇2R5 and-((: Η2χ302ΝΙ15Ι14) substituent substitution Where R4 and R5 are each as defined above for Ri, and 1 is 0, 2 or 3; and R4 and R5 are each independently as defined for Ri above. Within the scope of the present invention, compounds of formula (1) are also included Pharmaceutically acceptable salt

548271 A7 B7 5. Description of the invention (5) and its isomers, hydrates, isoforms and prodrugs. A preferred compound according to the present invention is a compound of formula (I), where A is selected from

R 15 〇 R14II l S-NII 〇 z2 21

R

o R 22

〇

z1 Z2

R8, R9, R10, R11, R12, R13, Rl4, r15, r16, and R17 are independently defined as above for R1 in the printed format of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, where each a substituent is a phenyl ring Depending on the situation and independently from any position of the phenyl ring, 1 or 2 are independently selected from η, CH3,-(CH2) qCF3, halogen, -CONR6R7, -COOR6, -COR6,-(CH2) rNR6R7, _ ( CH2) rCH3 (CH2) rSOR6,-(CH2) rS02R6 and this paper size are applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 548271 A7 B7 — —— _______ ------ _ V. Description of the invention ( 6)-(CH2) rS02NR6R7 is substituted by Z1 and Z2, wherein R6 and R7 are each independently as defined above for R1, and r is 0, 1 or 2; Q is selected from morphine, hexahydroether, and silo R1, R4 and R5 are each independently selected from the group consisting of fluorene, branched or straight-chain CVC4 alkyl, C3-C5 ring pit group 'C4_Cs (pit group-ring pit group), wherein the alkyl group is (^ -C〗 A cyclohexyl group is a C3-C6 ring fe group; a C6-C1G aryl group; and a heteroaryl group having 5 to 6 atoms selected from C, S, N, and 0; and wherein the aryl or heteroaryl group is visible Case and independently selected from 1 or 2 C Η 3,-(CH2) PCF3, halogen, -CONR5R4, -COOR5, -COR5,-(CH2) PNR5R4,-(CH2) pCH3 (CH2) pSOR5R4,-((: Η2) ρ802ί15 and-(CH2) pS02NR5 Substituted by substituents, in which R4 and R5 are each independently as defined above for R1, and p is 0, 1 or 2; printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, B is selected from phenyl, fluorenyl, and sulfonyl , Benzalanyl, dihydrobenzocranyl'benzophenylsulfanyl, ρ than p each group, succinyl, P-quinyl, iso-p-quinyl, cyclohexyl, cyclohexenyl , Cyclopentyl, cyclopentenyl, hydroindenyl, indenyl, tetrahydrofluorenyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, exofluorenyl and 4r , Each independently and independently from 1 or 2 selected from Η, CH3, CF3, _ prime,-(CH2) qCONR5R4,-(CH2) qNR5R4, (CH2) qCOR5, _ (CH2) qC02R5 and · OR5 Substituent substitution, wherein q is 0 or 1, and wherein R4 and R5 are each as defined above; R and R are each independently fluorene or methyl. A particularly preferred compound according to the present invention is a compound of formula (I), wherein ^ A is _____ —____ ~ 9 ~ this paper rule Degree Applicable to China National Standards (CNS) A4 (21〇χ 297 mm) 8 54 A7 Five —____ B7 Description of the Invention (7)

21 wherein R8 and R9 are ethyl groups, and the phenyl ring may be independently or independently selected from i or 2 at any position of the phenyl ring by i or 2 each selected from Η, ch3, _ (CH2) qCF3, halogen, -CONR6R7, -COOR6, -COR6, &quot; (CH2) rNR6R7,-(CH2) rCH3 (CH2) rSOR6,-(CH2) rS02R6 and _ (CH2) rS〇2NR6R7 are substituted by the substituents Z1 and Z2, of which R6 and R7 is each independently as defined above for R1, and r is 0, 1 or 2;

Ri is selected from the group consisting of fluorene, methyl, ethyl, 〇: Η2 (: ί1 = (: ΙΙ2, _ί: Ιί 2-cyclopropyl, -CHyaryl, or CH2-heteroaryl, the heteroaryl moiety has 5 to 6 atoms selected from C, S, N, and 0. Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, B is selected from phenyl, fluorenyl, fluorinyl, benzofuranyl, and dihydrobenzo Furyl, benzophenylthio, furyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, hydroindenyl, indenyl, tetrahydrofluorenyl, Tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, and oxazoline, each independently and independently selected from 1 or 2 selected from the group consisting of hydrazone, CH3, CF3, autogenin,-(CH2) qCONR5R4 ,-(CH2) qNR5R4, _ (CH2) qCOR5,-(CHDqCCbR5 and -OR5 are substituted with substituents, where q is 0 or 1, wherein R4 and R5 are as defined above; R2 and R3 are each independently fluorene or methyl The substituents A and B can be substituted at any position of the ring, respectively, as appropriate. "Halogen ·· means Cl, F, Br, and I groups. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 548271 A7 B7 five Description of the invention (8) "Aryl" means an aromatic ring with 6D_C atoms, such as phenyl and fluorenyl. ", Heteroaryl" means an aromatic ring whose fluorene or more (5-1 ) Atoms are elements other than C such as N, S and O. "Hydrogen aromatic" means a partially or fully saturated aromatic ring structure having 5 to 10 C atoms in the ring. "Heterohydroaromatic" means That is, in the ring, one or more (5-10) atoms are partially or fully saturated aromatic ring structures of elements other than C, such as N, S, and O. Isomers mean compounds of formula (I), where The functional groups have different positions and / or orientations. "Alignment" means stereoisomers, non-paraisoisomers, orthoisomers and paraisomers. "Anisoform" means formula (1 ) Among the compounds, those with different crystal lattices, such as crystalline compounds, are amorphous compounds. "Prodrugs" means pharmacologically acceptable derivatives, such as esters and amidines, such that the resulting biotransformation of the derivatives The product is an active drug. Goodman and Gllmans' reference book The pharmacological basis of Therapeutics, 8th edition, MCGraw_Hill Division Editor 1992, Biotransformation of Drugs "p.i3_i5, describing general precursor drugs, incorporated herein by reference. The novel compound of the present invention printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economics is useful for the treatment, especially for various pain conditions Such as chronic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain, etc. However, this list should not be construed as being limited thereto. The compounds of the present invention are used as immunomodulators, especially for Autoimmune diseases such as Guan Zhiyan 'are needed for skin transplantation, organ transplantation and similar surgery, for collagen 11 r-M male 548271 A7 ------ ~ ______ B7 V. Description of the invention (9) $ 白 病 Various allergies The disease is supplied as an antitumor agent and an antiviral agent. * The compound of the present invention is useful for disease states in which the opiate is present or involved in the typical disease and is degraded or disabled. This includes the use of the compounds of the present invention, diisotopically labeled transformants in diagnostic techniques and Imaging applications such as positron radiography (PET). The compounds of the present invention are used to treat diarrhea, depression, urinary incontinence, various psychological diseases, diarrhea, pulmonary edema, various gastrointestinal disorders, spinal cord injury and drug addiction, including 'oral alcohol, nicotine, opioids, and other drug abuse and For sympathetic nervous system disorders such as hypertension. The compounds of the present invention are used as analgesics for general anesthesia and monitoring anesthesia care I. Mixing with agents of different nature is often used to achieve the balance of effects required to maintain anesthetic complaints (such as forgetfulness, pain relief, muscle relaxation, and sedation). Included in this mix are inhaled anesthetics, hypnotics, scorching agents, neuromuscular blocking agents and sepals. The compounds of the invention are used as diagnostic agents in isotopically labeled forms. Also included within the scope of the present invention is the use of any of the compounds according to formula (I) above for the manufacture of a medicament for the treatment of any of the above. Another aspect of the present invention is a method for treating patients suffering from any of the above conditions, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, by administering an effective amount of a compound according to formula (G) above to a patient in need of such treatment. Production method &lt; The compound of the present invention can be prepared as follows. Mo Zhun (0 Yang) 8 4 specifications (21 0 '乂 297 mm) 548271 A7 B7 V. Description of the invention (10

Figure I

This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 548271 A7 B7 V. Description of invention (11 R ° Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Illustration II

M 2

1 N) / N-R (h

OH

This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 548271 A7 B7 V. Description of the invention (l2

Figure III R2- 〇 A, Guardian response -► + Y N I R1 ㈣ ⑹

A \ / B &quot; R3 I B—Z R1 (I) (P) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 15-Sasaki Coupling

This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 548271 A7 B7 V. Description of invention (l3

This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 548271 A7 B7 V. Description of the invention (l4) As shown in the diagram I &amp; II above, the preparation of the compound of formula (1) above can be borrowed. Dehydration of hydroxy compound (g) or (h) (where Ri, R2, R3, a &amp; b is as defined in above (I)). The subsequent dehydration of hydroxy compounds (§) or (11) (wherein R1, r2, r3, A and B are as defined in formula (I) above) can be carried out without solvent or in solvents such as water, alcohol, ester, HMPA, CH2C12 , Toluene, ether 嗣 i or in the presence of Br0ns ^ ecjt or Lewis acid such as H2S04, HC1, trifluoroacetic acid, A1C13, ZnC1 ^ in a cereal mixture, or In the presence of metal oxides such as Al203, Cr203, Ti02, W03, P205, or other dehydrating agents such as osmium, dimethyl sulfite, 'KHSO4', CuS〇4, g too Acid liver and the like. After or during the preparation of (I) from (g) and (h), the substituents Han 1, r2, and Han 3 and compounds A and B of formula (I), the substituents (as defined above) may be known by Modifications to techniques are exemplified in the literature, see new synthetic reactions such as Green's protecting group or House, which are well known to those skilled in the art. As shown, the pathway of I is illustrated, and the compound of formula (g) as described above can be prepared by using R1, R2 and R3 in formula (C) as the ketone defined in formula (I), and formula (€ ) The reaction between eight and six is as defined in formula (I), and X is a suitable group such as hydrazone, Cl, Br, I'OS02R and the like. The reaction can be carried out in a solvent-free or organic solvent such as THT, toluene, ether, dimethyl sulfoxide, or a solvent mixture, and treated with a suitable metal such as Mg, Li, Zu, Ca, Ce or the like. Treatment of halides such as Sml2, CrCl2, or the like is performed with organometallic agents such as sintered halide and mahogany clock.

Rl, R2, and R3 and the substituents on A and B of compound (g) (as defined above -17 &amp; paper size applies to China National Standards (CNS) A4 specifications (210X297 mm)) Please read the Ministry of Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 548271 A7 B7 V. The description of the invention (I5) can be modified after or during the reaction of organometallics, using methods known in the art (March, J., Advanced Organic Chemistry, Section 4 Edition, John Wiley &amp; Sons, 1992). Compounds of formulae (c) and (e) are commercially available, or by methods known in the art (March, J., Advanced Organic Chemistry, 4th edition, John Wiley & amp Sons, 1992). As shown in Scheme b of Scheme II, the compound of formula (h), as described above, can be prepared by the ketone of formula (1) (wherein R, R2 &amp; R3 &amp; B is as shown in formula ( 1) and the organometallic reagent of formula (j) (where A is as defined in formula (I) and M is a suitable metal group, such as Mg, Li, Zn, Cu, Ce, etc.) The reaction can be carried out without solvents or in organic solvents such as THF, toluene, benzene, dimethylsulfine or The solvent mixture is carried out. As shown in Route c of Figure II, the compound of formula can also be prepared by the carbonyl compound of formula (I) (wherein R1, R2 and R3 are as defined in formula (1), and X is an appropriate free group such as Cl, Br, OH, OR, SR, NR2, N (OR ') R and the like and an organometallic reagent of formulas (J) and (k) (wherein eight and 6 are as formula (I ) And M is a reaction between a suitable metal group such as] y [g, Li, Cu, Ce, etc.). The reaction can be solvent-free or in a solvent such as THT, a member of the Central Standards Bureau of the Ministry of Economic Affairs, X Consumer Cooperative. Printing, ether, monomethylformamide, dioxane, dimethyl sulfoxide or in a solvent mixture. R1, R2 and R3 and the substituents on A and B of compound (h), as defined above, in After or during the organometallic reaction, it can be modified by methods known in the art and exemplified in the literature, see, for example, the protective group of Green or the new type of synthetic reaction of House, which are well known to those skilled in the art. -18 -This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 548271 A7 B7 V. Description of Invention (l6) Formula (i), Compound j), (k) and (1) it is commercially available or prepared by techniques known in the arts (March, J., Advanced Organic Chemistry, 4th ed in, John Wiley &amp; Sons, 1992). As shown in Figure III, the preparation of the compound of formula U) above can be obtained from ethylene halide (0) (X = Br, I) and borane, borate (P), in a base such as Na2C03, K2C03, KK3PO4, triethylamine, CsF, NaOH or alkoxide and Pd catalysts such as (PPh3) 4Pd, bis (diethyleneglycol) Pd (〇), Pd / C and PPh3; Pd (II) species Catalysts that can also be used include: (pph3) 2PdCl2,1,4-bis (diphenylphosphinobutane) palladium (II) chloride, palladium acetate, bis (acetonitrile) palladium (Π) chloride, dichloro [1 , 1 ′ · bis (diphenylphosphino) ferrocene] palladium (II) and suzaki coupling in the presence of palladium acetate-tris (0-tolyl) phosphine, where R1, R2, R3, A and B is as defined in the above formula (I). Sasaki coupling reaction can be performed in toluene, xylene, anisole, DMF'THF, alcohol, ether, water or solvent mixture. The compound of formula (P) is printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, where B is as defined in formula (I) and Z is B (0H) 2, which can be obtained commercially or from hydrolysis of borate . Compounds of formula (p), where B is as defined in formula (I) and Z is B (OR) 2 (R = Me, Et), can be prepared from the reaction of a compound of formula BM with B (0R) 3, where R = Me or Et, and M are suitable metal-based Li or Mg or the like. A compound of formula (ρ), wherein B is as defined in formula (I) and Z is a 9-borabicyclo [3,3,1) nonane (9-BBN) , 1] Prepared by the reaction of nonane. Substituents R1, R2, R3 and the $ -generation groups (as defined above) on A and B of formula (I) after or during the preparation of (I) from (0) and (P), may be known by the The method or the method exemplified in the literature can be modified by referring to, for example, a protective group of Gree η or a novel synthetic reaction (known to those skilled in the art). Exactly, the Zhang scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 548271 A7. Description of the invention (17 As shown in Figure II, in the formula (°), X is a compound of Br or I, but It is prepared from R'R'11 in formula (η) and the compound as defined in formula (1). Elimination is performed. Toothing is performed in a solvent such as CH2Cl2, CHCl3, ccu, dichloroethane or acid. The odor or base is the self-chemical agent. The subsequent elimination step is performed in a solvent such as water, alcohol DMF_, using NaOH, kOh, metal alkoxide or triethylamine. As shown in Figure III As shown, the compound of formula (η), as described above, may be the same as that of formula (C), wherein R1, R2 and R3 are as defined in formula (I) and the reagent of formula (I), where A is as in formula (I) Ashikaga and γ are suitable for the preparation of the phytotetraphytic reaction of phosphonate scale salts. The eotepic reaction can be known in the art and exemplified in the literature ⑽ L Ad 遍 ced Organic Chemistry, 4th edition, j〇hn 丽 巧 &amp; 1992). Under various conditions. The reagents of the formulae (C) and (m) are commercially available, or by methods known in the art (March, J., Advanced Organic Chemistry, 4th Edition, John Wiley &amp;

Sons, 1992). (t) (where R1, R2, R3, r12 are as shown in Figure IV above, the compound of formula (u) can be removed by the hydroxy compounds 13 and B as defined above)

R The Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs were obtained in print. The dehydration step can be carried out without solvent or in a solvent such as water, alcohol, ester HMPA, dCh, toluene, ether, ketone, leptin, or in a solvent mixture in Bernst or Lewis acid such as H2S04, HC1 , Trifluoroacetic acid AICI3, ZnCh or the like, or in the presence of metal oxides such as human 1203 203 Ti02, W03, P205, or other dehydrations such as I2-methylene Obstacle, KHSO4, CuS04, g too acid liver and the like.

548271 Printed by A7 B7, Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 5. Description of the Invention (18) Substituents R1, R2 and R3 of Compound (U) and Substituent B (as defined above); Prepared from (t) (U) After or during, it can be modified by methods known in the art and exemplified in the literature 'see, for example, the protective group of Green or the new synthetic reaction of House (known to those skilled in the art). As shown in Figure IV above, the compound of formula (t) can be selected from compounds R1, R2, R3, R13, and B in compound (s) as defined above, and used with a halogenated halogen such as MeI, such as NaOH, and a phase transfer agent such as It is obtained by the amination reaction in the presence of BimNHSO4. The compound of formula (s) can be prepared by the ketone of formula (r), where r1, R2, R3, as defined above, and the organometallic reagent of formula (k), where b is as defined in formula (I), and M It is a reaction between suitable metal groups such as Mg, Li, Zn, Cu, Ce and the like. The reaction can be carried out without a solvent or in a solvent such as τ η f, toluene, ether, dimethylformamide, diuridine, dimethylsulfoxide or a solvent mixture. The substituents R1, R2, R3, and Ri3 of the compound (s) (defined above) can be obtained by methods known in the art and methods exemplified in the literature. See, for example, Greeni protecting groups or the new-type synthetic reaction of House (well-known here) Taoist), modified after or during the preparation of (s) from (r) and (k). As shown in Figure IV, the compound of formula (0) can be prepared by the carbonyl compound of formula (1), where Ri, R2 and R3 are as defined in formula (1), and χ is an appropriate free group such as Cl, Br , OH, OR, SR, NR2, is ^ OR1)! ^, Followed by organometallic reagents (by defining compound (q) where R13 is as defined above, first treated with a base such as NaH, followed by subsequent use of an alkyl lithium such as Buli Metal transfer effect). The reaction can be carried out in a solvent such as THF, toluene, acid, dimethylformamide, diazane or in a solvent mixture. Compound (r) (please read the precautions on the back before _ page): binding

54827l A7 ___B7 V. The substituents Ri, R2, and R3 of the description of the invention (I9), as defined above, can be learned by techniques and examples exemplified in the literature. 'See, for example, the protective group of Gree η, or η 〇use New-style synthesis reactions (familiar with those who are skilled in this way) are modified after or during the preparation of (r) from (q) and (丨). As shown in Diagram IV, the compound of formula (q) can be obtained by the tritiated reaction of 4-iodoaniline using hepatic or fluorenyl chloride in an organic solvent such as CHgCl2. The substituent R13 of the compound (q) is as defined above. The invention is illustrated in more detail by the following examples, which are not intended to limit the invention. A) Synthetic scheme of the compounds of Preparation Examples 1-7 The compounds of Examples 1-7 are prepared according to the method shown in Scheme 1 below. Figure 1

2 B N C〇2Et

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 〇Me

I

Me

t-BuLi 1 · Boc2〇 2. Me (MeO) NH 1 Η ⑴ • Bu PrMgCI 1 巳 oc (2)

548271 A7 B7 V. Description of the invention (2〇

ArLL

NEt, 2

NEt0 Η

巳 OC

Ar = naphthyl (4); A "= 2,6-xylyl, (5)

Ar = phenyl, (6) Example 1 Ar = l-fluorenyl, (7) Example 2 A "= 2,6-xylyl, fluorene example

NEL

Printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, NIR ^

Ar = Ph, R = PhCH2, (10) Example 5 Ar = Ph, R = Cyclopropylmethyl, (12) Example 7 Ar = Ph, R = 2,3-Epoxypropyl, (11) Example 6 A "= naphthyl, 1 ^ = propyl, (9) Example 4 Preparation of oxycarbonyl N'-methyl-N'-methoxy-isopiperidinamide (compound 2) f Ester (compound 1) (4.71 g, 30.0 mmol), di-tert-butyl dicarbonate (6.55 g, 30.0 mmol) and Na2C03 (4.77 g, 45 mmol) in H20-THF (90 (10 ml) was refluxed for 2 hours. The reaction mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with brine and dried over MgSCh. The solvent was removed to give isopiperidinyl tert-butoxycarbonyl ethyl ester. (7.67 grams): __ ^ 23-&quot; ^ Zhang scales are applicable to China's national standard (CNS) A4 specifications (210 x &quot; 297 mm) '548271 A7 B7 V. Description of the invention (21) dH (400 MHz, CDCl3) 1.25 (t, J = 7.2 Hz, 3H), 1.45 (s, 9H), 1.62 (m, 2H), 1.87 (m, 2H), 2.43 (m, 1H), 2.84 (m, 2H), 4.02 (m, 2H), 4.13 (q, J = 7.2 Hz, 2H); dc_13 (100 MHz, CDCl3) d: 14.0, 27.8, 28.2, 40.9, 42.9, 60 · 2, 79.2, 154.4, 174.2. Will be on The N-tertiary butoxycarbonyl ethyl isopiperidinate was dissolved in anhydrous TF (60 liters) and mixed with NHMe (OMe) HCl (4.39 g, 45.0 mmol). The mixture was mixed with i-PrMgCl (2.0M In DHF, 45 ml, 90 millimolar), treated at -20 ° C, the resulting solution was -5. (: Stirred for 1 hour, the reaction was stopped with NH4C1 aqueous solution, and then ethyl acetate (2 X 1 0 0 Ml) extraction. The combined organic layers were washed with brine and dried over MgS04. The solvent was removed to obtain N-tertiary butoxyl N'-methyl-N'-methoxy-isopropyl lake g (a compound 2) (8.0 g, 98%): β h (400 MHz, CDC13) 1.30 (s, 9H), 1.54 (m, 4H), 2.65 (m, 3H), 3.02 (s, 3H), 3.56 (s , 3H), 3.99 (brs, 2H); d c_13 (100 MHz, CDC13) c5 \ · 27.7, 28.1, 32.0, 37.8, 43.1, 61.3, 79.1, 154.4, 176.0. (Ii) l- (4'_N ' , N'-Diethylaminecarbonylphenylfluorenyl) -N · Third-butoxycarbonylhexapyridine (Compound 3) Production of Central Standards Bureau, Ministry of Economic Affairs, Consumer Cooperatives, India Ethylbenzidine (9.09 g, 30.0 mmol) and TMEDA (6.96 g, 60 · 0 mmol) in anhydrous THF (60 ml In the solution was added tert-butyl lithium (35.0 ml, 1 · 7Μ, 60 · 0 mmol) (at a 78Ό). After 30 minutes, N-tert-butoxycarbonylmethyl-N, -methoxyisopiperidinamide (Compound 2) (8.0 g, 29.4 mmol) (in THF (10 ml)) was added dropwise. The reaction mixture was warmed to room temperature (r · t ·) and then stopped with NH ^ Cl solution. The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 548271 A7 B7 V. Description of the invention (22 Reaction, with HC1 ( (Concentrated, 20 ml) and neutralized with C, extracted with ethyl acetate (2 X 100 ml). The combined organic layers were washed with brine and dried over MgS04. The solvent was removed to obtain the crude product, which was purified by a silica gel column. Dissolve with MeOH-CH2C12 (2:98) to obtain 4- (4'-N ', N'_diethylaminecarbonylphenylfluorenyl) _N-third butoxycarbonylhexahydropyridine (compound 3) (3 · 15 G, 28%): dH (400 MHz, CDCl3) 1.08 (brs, 3Η), 1.23 (brs, 3H) 1.43 (s, 9Η), 1.61 (m, 2H), 1.80 (m, 2H), 2.89 (m , 2H), 3.20 (brs, 2H), 3.40 (m, 1H), 3.53 (brs, 2H), 4.11 (brs, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.94 (d, J = 8.0 Hz, 2H) 〇 (iii) 4- (a-¾-yl-α (4-N-third butoxalyl hexahydro p-pyridyl) -a-(1-naphthyl) methyl) -N, A solution of N-diethylbenzoic acid amine (compound 4) in 1-bromofluorene (0.52 g, 2.5 mmol) in anhydrous THF (10 ml), plus n-butyllithium (1.1 ml, 2 5M, 2.75 millimolar) (at -78 ° 0). 30 minutes, 4- (4'-1 ^ '3, -diethylaminecarbonylphenylfluorenyl) -cardia third butoxycarboxyhexade Hydropyridine (compound 3) (776 mg, 2.0 mmol. In 2 ml of THF). The reaction mixture was warmed to rt and then quenched with NH4C1 aqueous solution, and extracted with ethyl acetate (2 × 50 ml). The combined organic layers were treated with It was washed with brine and dried on Mg SCU. The solvent was removed to obtain the crude product, which was purified on a silica gel column and dissolved in MeOH-CH2Cl2 (0.5: 99.5-5:95) to give 4_ (α-hydroxy-α-(4 · Ν -Third-butoxycarbonylhexahydropyridyl)-"-(1-fluorenyl) · methyl) -N, N · diethylbenzidine (Compound 4) (760 mg, 74%): mp 121- 124 ° C (CH2C12);

Vma / KBiOcm-1 3402, 2960, 1685, 1626, 1425, 1283, 1160; -25-This paper size applies to China National Standard (CNS) A4 size (210X297 mm) Please read the note on the back before binding Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 548271 A7 B7 V. Description of the Invention (23) Analysis of the calculation of C32H40N2O4, 0.550 Η 20; C, 73.11; Η, 7.86; N, 5.33 〇 Actual measurement: C, 72.86; Η, 7.64; N, 5.26; β h (400 MHz, CDC13) 1.03 (brs, 3H), 1.16 (brs, 3H), 1.18-1.35 (m, 3H), 1.95 (m , 1H), 2.60 (m, 2H), 2.75 (brs, 2H), 3.15 (brs, 2H), 3.42 (brs, 2H), 4.10 (brs, 2H), 7.10-7.50 (m, 7H), 7.75 ( m, 3H), 8.27 (brs, 1H); ^ C-i3 (100MHz, CDCl3) d: 12.8, 14.1, 27.1, 27.2, 28.4, 39.2, 43.3, 45.4, 79 · 3, 80.4, 124.1, 124.9, 125.2, 125.3, 126.0, 127.3, 128 · 8, 129.2, 131.4, 135.0, 135.2, 139.4, 146.5, 154.6, 171.0. (iv) borrowed from 4- (α hydroxy-α (4 · N-third butoxycarbonyl hexahydropyridine) -2.6-dimethylbenzyl-N, N-diethylbenzidine (compound 5) For the method described for compound 4, except using 2-bromo-m-xylene; (749 mg, 76%): mp 92-96 ° C (CH2Cl2); i / ma / KBiOcnT1 3451, 2970, 1690, 1631 , 1425, 1165; Analysis of the calculation of C3OH42N204, 0.550Η20; C, 71.54; H, 8.61; N, 5.56. Printed measurement by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs: C, 71.70; H, 8.34 N, 5.62; βΗ (400 MHz, CDC13) 1.10 (brs, 3H), 1.21 (brs, 2H), 1.32 (m, 2H), 1.43 (s, 9H), 1.69 (m, 1H), 1.77 (m , 1H), 2.32 (s, 6H), 2.47 (s, 1H), 2.75 (m, 3H), 3.25 (brs, 2H), 3.51 (brs, 2H), 4.13 (brs, 2H), 6.91 (m, Name H), 7.00 (m, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H); c_13 (100 MHz, CDCl3) d: 12.6, 14.0, 25.0, 27.7, 28.2, 39.1, 42.9, 43.1, 44.4, 53.3, 79.1, 83.0, 125.8, 126.3, 127.2, 131.2, 135.3, 136.7, 142.9, 147.8, This paper size applies to China National Standard (CNS) A4 specifications (210X297) (%) 548271 A7 B7 V. Description of the invention (24) — 154.5, 170.7 〇 Example 1 Preparation of monoethyl (phenyl-hexahydropyridine_4_ylidenemethylbenzidine (house 6) f in 4 · ( α_Hydroxy · α · (4-N_Third-butoxycarbonylhexahydropyridyl) · fluorenyl) -N, N · Diethylbenzyl ^ (932 mg, 20 mmol) in anhydrous ch2C12 (10¾ liters The solution in) was added with trifluoroacetic acid (100 ml) under rt ·. The reaction mixture was stirred at rt · for 16 hours and then concentrated. The residue was dissolved in Ac0Et (100 ml). The resulting solution was IN NaOH solution, NH4C1 The aqueous solution and brine were washed and dried on MgSCU. The solvent was removed to obtain a crude product, which was purified on a silica gel column and dissolved in MeOH_CH2Cl2 (20:80) to obtain ("-phenyli_ (4_N, N'-diethylaminecarbonyl). Phenyl) _4_methylene-hexahydroρ ratio (Compound 6) (632 mg, 91%); dH (400 MHz, CDCl3) 1.08 (brs, 3Η), 1.17 (brs, 3Η), 2.29 (m, 4Η), 2.86 (m, 4H), 2.94 (brs, 1H), 3.24 (brs, 2H), 3.47 (brs, 2H), 7.09 (m, 4H), 7.15 (m, 1H), 7.24 ( m, 4H); dc-13 (100 MHz, CDCl3) d: 12.6, 14.1, 32.7, 32 · 8, 39.1, 43.2, 47.9, 126.0, 126.4, 12 7.9. 129.6. 134.9, 135.4, 135.9, 141.7, 143.2, 171.1. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Hcl salt: m.p. 110-120 ° C (AcOEt-Ether-CH2Cl2);

PmaxCKBOcm · 1 3440, 2970, 1617, 1438, 1289; Analytical pair (: 231128 ^ 0.1.0 11 (: 1, 1, 0.50 (: 112 (: 12, 0. &lt; 251120) calculation; C, 65.35; H , 7.12; N, 6.49. Measured 値: C, 65.14; H, 7.08; N, 6.55. Example 2 _-27-This paper size applies to China National Standard (CNS) A4 (21 OX297 mm) &quot; &quot; 548271 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention (25) N, N-diethyl-4 _ (1-naphthyl nitrogen ρ Biyodo-4-subunit-methyl) The preparation of phenylamidine (compound 7) was carried out as described for Example 1, using compound 4; (226 mg, 71%); mp 80-85 ° C (MeOH-CH2Cl2); i / maxCKBOcm · 1 3052, 2970, 1628, 1431, 1286; Analyze the calculation of C27H3 () N2O.0.20CH2a2; C, 78.62; H, 7.37; N, 6.74. Found: C, 78.63; H? 7.07; N? 6.54; d H (400MHz, CDCl3) 1.06 (brs, 3H), 1.16 (brs, 3H), 2.00 (m, 2H), 2.53 (m, 2H), 2.64 (brs, NH), 2.77 (m, 2H), 2.97 (m, 2H), 3.20 (brs, 2H), 3.47 (brs, 2H), 7.26 (m, 5H), 7.43 (m, 3H), 7.74 (m, 2H), 8.0 (m, 1H); dc_13 (100 MHz, CDCl3) d: 12.8, 14.1, 32.6, 33.5, 39.1, 43.2, 47.9, 48.2, 125.5, 125.7, 125.8, 126.1, 127.1, 127.2, 129.1, 131.9, 132.5, 133.8, 135.1, 138.3, 139.8, 142.6, 171.1. Example 3 The preparation of N, N-diethyl-4- (2,6-xylyl-7T chlorop-pyridine_4-ylidene-methyl) -benzidine (compound 8) is as follows The method described in Example 1, using compound 5 (242 mg, 80%); its HC1 salt; decomposition &gt; 115 ° C (AcOEt-ether_CH2C12); vmax (KBr) cm-1 2970, 2725, 1590, 1464, 1290, 1101; Analyze the calculation of C25H32N2O.1.0 HC1, 0.50CH2C12, 0.5 A 2 0; C, 65.94; A, 7.60; N, 6.03 0 Found: C, 65.98; A, 7.37; N , 5.81. 28 This paper size applies to Chinese National Standard (CNS) A4 (210X 297mm). Please read the back notice first.

Binding 548271 A7 B7 V. Description of the invention (26) Example 4 Ν, Ν · —ethyl-4 · (1-nayl-isopropylhexazine ρβ-4-ylidene-methyl) -benzidine (Compound 9) Production of (α-(1-fluorenyl) -α _ (4_N ', N, -diethylaminecarboxyphenyl))-4-methylenehexahydropyridine (Compound 7) (125 mg ), A mixture of allyl bromide (90 mg) and K2C03 (138 mg) in MeCN (10 ml) was stirred at rt · for 14 hours, then the reaction was stopped with IN NH4OH solution, and extracted with AcOEt (100 ml). The organic phase was washed with an aqueous NH4C1 solution, brine, and dried over MgS04. The solvent was removed to obtain a crude product, which was purified on a silica gel column and dissolved in MeOH-CH2C12 (2:98) to obtain ("-(I · fluorenyl) -from- (4-N ', N'-diethylamine carbonyl Phenyl) -4-methylene-N-allyl hexahydropyridine (50 mg, 36%); dH (400 MHz, CDCl3) 1.08 (bi: s, 3H), 1.19 (bi: s, 3H) , 2.08 (π, 2H), 2.39 (m, 2H), 2.61 (m, 4H), 3.01 (m, 2H), 3.24 (brs, 2H), 3.52 (brs, 2H), 5.13 (m, 2H ), 5.90 (m, 1H), 7.27 (m, 5H), 7.45 (m, 3H), 7.80 (m, 2H), 8.04 (m, 1H); (ic_13 (100 MHz, CDCl3) e: 12.8, 14.1 , 30.9, 32.0, 39.1, 43.2, 54.7, 54.9, 61.5, 117.8, 125.4, 125.6, 125 · 8, 126 · 0, 127.1, 128.2, 129.1, 131.8, 132.4, 133.7, 135.0, 138.0, 139.8, 142.6, 171 .Bull prints its HC1 salt by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs: mpllO-120 ° C (AcOEt-ether-CH2C12); vmax (KBr) cm-1 3416, 2961, 1620, 1430, 1288; Analysis of C3 〇H34N20.1.0 Calculated HC1, 0.5〇CH2Cl2, 0.25Η20, 値; c, 70.17; H, 7.05; N, 5.37 实 measured 値: C, 70.15; H, 6.92; N, 5.24. This paper size applies Chinese National Standard (CNS) Α4 Specification (210X297 mm) 548271 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (27) Example 5 N, N Diethyl-4-(phenyl-N — ^ based fine 7T chlorine outside Dyme-4-ylidene-methyl) benzidine (Compound 10) was prepared as described in Example 4, using compound 6 and benzyl bromide (2 15 mg, 98%); dH (400 MHz, CDCl3) 1.09 (brs, 3H), 1.19 (brs, 3H), 2.37 (m, 4H), 2.47 (m, 4H), 3.25 (brs, 2H), 3.50 (brs, 4H), 7.0-7.30 ( m, 14H); dc_13 (100 MHz, CDCl3) tf: 12.7, 14.0, 31.6, 39.1, 43.1, 54.9, 55.0, 62.8, 125.9, 126.2, 126.8, 127.8, 128.0, 128.9, 129.6, 129.7, 134.9, 135.0, 136.3, 138.2, 141.9, 143.3, 171.0. Its HC1 salt: mp230-245 ° C (AcOEt-ether-CH2C12); i / max (KBr) cm_1 3423, 2976, 1624, 1434, 1288; Analyze the calculation of C30H34N2O.1.0 HC1, 0.25CH2C12, 0.25H2O 値C, 72.55; H, 7.25; N, 5.59. Found 値: C, 72.38; H, 7.16; N, 5.50. Example 6 The preparation of N, N-diethyl-4- (N-2,3-soil milk acryl ^ -phenyl-nitrogen 4 subunit-methyl) -benzidine (compound 1 1) For the method described in Example 4, use compound 6 and epibromohydrin (102 mg, 84%); dH (400 MHz, CDCl3) 1.10 (brs, 3H), 1.20 (brs, 3H), 2.28 (m, 1H ), 2.39 (m, 4H), 2.45 (m, 1H), 2.54 (m, 2H), 2.61 (m, 2H), 2.74 (m, 2H), 3.09 (m, 1H), 3.26 (brs, 2H) , 3.50 (brs, 2H), 7.10, 4H), 71.5 (m, 1H), 7.25 (m, 4H); dc_13 (100 MHz, CDC13) cJ: 12.8, 14.1, 31.4, This paper is applicable to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the notes on the back before clicking this page), binding and ordering 548271 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (28 ); 39.1, 43.2, 44.9, 50.1, 55.5, 60.8, 126.0, 126.4, 127.9, 129.6, 129.7, 135.0, 135.3, 135.7, 141.8, 143.2, 171.1 〇 Example 7 Ν, Ν-Diethyl-4- (1 -Cyclopropylmethyl-phenyl-hexahydropyridine-4-methylene-methyl) -benzidine (Compound 12) was prepared as described in Example 4 using the compound 6 and cyclopropylmethyl chloride (104 mg, 86%); dh (400 MHz, CDCl3) 0.20 (m, 2H), 0.59 (m, 2H), 1.04 (m, 1H), 1.14 (brs, 3H), 1.24 (brs, 3H), 2.48 (d, J = 6.4 Hz, 2H), 2.56 (brs, 4H), 2.80 (brs, 4H), 3.29 (brs, 2H), 3.53 (brs, 2H), 7.14 (m, 4H), 7.22 (m, 1H), 7.27 (m, 4H); dc_13 (100 MHz, CDCl3) d: 4.18, 7.3, 12.8, 14.1, 30.3, 39.2, 43.2, 54.3, 62.7, 126.2, 126.6, 128.0, 129.5, 129.6, 134.1, 135.3, 136.3, 141.5, 142.9, 171.0. Its HC1 salt: decomposes 2100 ° C (AcOEt-ether-CH2C12); v max (KBr) cm-1 3027, 2359, 1620, 1439, 958; analysis of C27H34N2O.1.0 HC1, 0.5 CH2Cl2, 0.75H2O Calculated 値; C, 66.73; H, 7.64; N, 5.66. Measured 値: C, 66.60; H, 7.45; N, 5.78. B) Scheme for the preparation of the compound of Example 8 The method for the preparation of the compound of Example 8 is shown in Scheme 2 below. This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) (please read the precautions on the back before _ horse page) &quot; 口 548271 A7 B7 V. Description of the invention (29) Figure 2

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back first, then _ 舄 this page). Product 13) Prepared in 2,3 · benzofuran (295 mg, 2.5 mmol) in anhydrous D11 Solution in thorium (10 ml), plus tertiary butyl lithium (1.5 ml, 1.7 M, 2.5 millimolar) The paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 548271 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by Consumer Cooperative A7 B7 V. Invention Description (30)) (under -78C). After 30 minutes; N-third butoxycarboxyl N-methyl-N-methoxy-isopyridamidine (544 mg, 2.0 mmol) (in 2 ml of THF) was added dropwise. The reaction was stopped at rt with N 以 4 C1 aqueous solution and extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with brine and dried over MgSO. The solvent was removed to obtain a crude product, which was purified on a silica gel column and dissolved in MeOH-CH2Cl2 (5:95) to obtain 4- (2-benzofuranyl) -N-third-butoxycarboxyhexahydro-p-pyridine (13 ) (456 mg, 69%). β H (400 MHz, CDC13) 1.46 (S, 9H), 1.75 (m, 2H), 1.91 (m, 2H), 2.91 (m, 2H), 3.37 (m, 1H), 4.20 (brs, 2H), 7.29 (m, 1H), 7.46 (m, 1H), 7.53 (s, 1H), 7.56 (m, 1H), 7.69 (m, 1H); ec_13 (100MHz, CDCl3) d: 27.8, 28.3, 43.1, 44.4, 79.5, 112.3, 112.9, 123.1, 123.8, 126.9, 128.2, 151.8, 154.5, 155.5, 192.8. (ii) 4- (to-hydroxy-third-butoxycarbonylhexahydropyridyl) -2-benzofuranyl) -N, N-diethylbenzidine (compound 14) is prepared as for compound 4 Said method, using 4-iodine · N, N · diethylbenzamide (425 mg, 61%); mp 102-106 ° C (CH2C12);

VmaxCKBOcm · 1 3362, 2970, 1690, 1617, 1425, 1288, 1160; θ η (400 ΜΗζ, CDC13) 1.06 (brs, 3Η), 1.20 (brs, 3Η), 1.24 (m, 2Η), 14.6 (m, 11H), 2.42 (m, 1H), 2.58 (brs, 2H), 3.20 (brs, 2H), 3.50 (brs, 2H), 4.05 (brs, 2H), 4.37 (s, 1H), 6.70 (s, 1H ), 7'16 (m, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.58 (d , J = 8.0 Hz, 2H); dc_13 (100 MHz, CDCl3) e: 12.6, 13.9, 25.5, 26.3, 28.2, 39.0, 43.1, 44.9, 77.3, 79.0, 103.3, 110.9, 120.6, 122.5, this paper Zhang scale applies Chinese National Standard (CNS) Α4 specification (210X297 mm) (Please read the precautions on the back before filling this page) r equipment_

1T 548271 A7 B7 V. Description of the invention (31 123.5, 125.6, 125.8, 127.9, 135.3, 144.0, 154.4, 154.5, 160. 5, 170.9 〇 Example 8 N, N-diethyl-4- (2-benzo Furan-hexahydropyridine-4-ylidene-methyl) -benzidine (compound 15) was prepared as described in Example 1 using compound 14 (135 mg, 0%); dh (400). MHz, CDCl3) 1.20 (brs, 3H), 1.24 (brs, 3H), 2.36 (brs, 2H), 3.00 (brs, 4H), 3.15 (brs, 2H), 3.33 (brs, 2H), 3.56 (brs, 2H), 4.45 (brs, 1H), 6.25 (s, 1H), 7.24 (m, 4H), 7.41 (m, 4H); d c_13 (100 MHz, CDC13): 12.9, 14.2, 29.6, 32.0, 32.4, 39.3, 43.4, 47.2, 107. 4, 110.0, 120.7, 122.7, 124.2, 126.0, 126.5, 128.2, 129.9, 136.1, 139.5, 140.5, 154.4, 156.2, 171.0. Its HC1 salt: 120 ° of decomposition C (AcOEt_ether-(: 112 (: 12); V max (KBr) cm_1 2977, 2801, 1586, 1449, 1257. C) Preparation Example 9-10 Synthesis of Compounds Illustrated Preparation of Examples 9 and 10 Compounds, according to The method shown in Figure 3 is shown below. Please read the note printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 548271 A7 B7 V. Description of invention (32 Figure 3

X = F, (16) X = Cl, (17) 〇

NEt2 X = F, (18) X = Cl, (19) X = F, (20) X = Cl, (21)

O

Preparation of 4 · (4-fluorophenylfluorenyl) hexahydropyridine hydrochloride (Compound 16) (Compound 16) 2.44 g, 10.0 mmoles), di-tert-butyl dicarbonate (2.18 g's 10.0 mmoles) and Na2C03 (1.59 g, 15 mmoles) in H2O-THF (50/5 The mixture was refluxed for 1 hour. The reaction mixture was extracted with ethyl acetate &lt; (2 x 100 ml). The combined organic layers were washed with brine and dried over MgSO. The solvent was removed to obtain 4- (4-fluorophenylfluorenyl) -N-tert-butoxycarbonylhexahydropyridine (OB701_31, 2.28 g, 74%); -35 This paper size applies the Chinese National Standard (A4) specification (21〇 X 297 mm) 548271 A7 B7 V. Description of the invention (33) mp 80-83 ° C (CH2C12); i / max (KBr) cm-1 2980, 2842, 1680, 1587, 1416, 1160; h (4〇 〇MHz, CDC13) 1.44 (s, 9H), 1.69 (m, 2H), 1.79 (m, 2H), 2.87 (m, 2H), 3.34 (m, 1H), 4.13 (brs, 2H), 7.12 (m , 2H), 7.95 (m, 2H); dc_13 (100 MHz, CDCl3) (i: 27.4, 28.4, 43.2, 43.4, 79.6, 115.8, 115.9, 130.8, 130.9, 132.2, 154.6, 164.4, 166.9, 200.4. ( ii) 4- (4-chlorophenylfluorenyl) -N-tert-butoxycarbonylhexahydropyridine (compound 19) was prepared as described for compound 18 using compound 17 (1.23 g, 85%); mp 122 -125 ° C (CH2C12); y mJKBiOcm-1 2970, 2842, 1680, 1582, 1420, 1200; β h (400 MHz, CDC13) 1.47 (s, 9H), 1.69 (m, 2H), 1.81 (m, 2H), 2.90 (m, 2H), 3.36 (m, 1H), 4.18 (brs, 2H), 7.44 (m, 2H), 7.88 (m, 2H); dc_13 (100 MHz, CDCl3) d: 28.3, 28.4 , 43.2, 43.4, 79.6, 129.0, 129.6, 134.1, 139.4, 154.6, 200.7 〇 (iii) 4 (π -Chenyl group-π (4-N -Second butoxy alkynyl 7T Chlodendyl) -4 monofluorofluorenyl) -N, N -Preparation of diethylbenzamide (compound 20) as described for compound 4, using compound 18 and 4 -._ N, N · diethylbenzamide (454 mg, 47%); mp 84-86 〇C (CH2Cl2); i / max (KBr) cm-1 3421, 2970, 1685, 1612, 1430, 1288, 1165; dH (400 MHz, CDCl3) 1.13 (brs, 3H), 1.23 (brs, 3H), 1.32 (m, 4H), 1.44 (s, 9H), 2.48 (m, 1H), 2.68 (brs, 2H), 3.26 (brs, 2H), 3.54 (brs, 36) This paper standard applies to Chinese National Standard (CNS) A4 specification (210X 297mm) Please read the notes before binding and print 548271 printed by the Employees 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed A7 B7 printed by the Staff's Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (34) 2H), 3.57 (s, 1H), 4.11 (brs, 2H), 6.96 (m, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.44 (m, 2H), 7.47 (d, J = 8.0 Hz, 2H ); dc_13 (100MHz, CDC13) d: 12.9, 14.0, 26.2, 28.2, 39.1, 43.2, 43.6, 44.3, 78.9, 79.1, 1 14.5, 114.7, 125.7, 126.1, 127.5, 127.6, 135.0, 141.2, 146.9, 154.5, 160.0, 162.5, 170.9. (iv) 4-π-¾-yl-α-(N-third butoxalyl hexahydro p-pyridyl)-4-chloro (methylene) -N, N-diethylbenzidine (Compound 21 ) Preparation: The method described for compound 4 'with compound 19 and 4-N-N, N-diethylbenzamide (626 mg, 63%): mp 100-105 ° C (CH2C12); p max (KBr) cm_1 3411, 2970, 1685, 1617, 1425, 1288, 1165, 1092; dH (400 MHz, CDCl3) 1.08 (brs, 3H), 1.20 (brs, 3H), 1.33 (m, 4H ), 1.44 (s, 9H), 2.44 (m, 1H), 2.63 (brs, 2H), 3.22 (brs, 2H), 3.49 (brs, 2H), 3.99 (s, 1H), 4.05 (m, 2H) , 7.20 (ιη, 4H), 7.39 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H); cJ 〇13 (100MHz, CDC13) d: 12.5, 13.9 , 25.9, 28.1, 39.0, 43.0, 44.1, 78.7, 79.0, 125.6, 126.0, 127.2, 127.8, 131.9, 134.8, 144.1, 146.6, 154.3, 170.7. Example 9 Preparation of N, N-diethyl-4- (4-fluorophenyl-hexahydropyridine · 4 · ylidene-methyl) -benzidine (Compound 22) was performed as in Example 1 (Compound 6). Said method, using compound 20. Towel-face calling MHz, CDC13M 1.12 (3 H, br m, CH3CH2-), 1.24 (3 H, br m, CH3CH2-), 2.32 (4 H, m, hexahydropyridine Cii_), 2.54 (1 H, br m ， -37-This paper size applies Chinese National Standard (CNS) A4 specification (21〇 &gt; &lt; 297mm) (Please read the precautions on the back before filling this page) -mouth m 548271 A7 B7 V. Description of the invention (35) NH), 2.91 (4 H, m, hexahydropyridine CK ·), 3.27 (2 H, br m, CILN-), 3.52 (2 H, br m, CILN ·), 7.00 ( 2 H, m, ArH), 7.09 (2 H, m, ArH), 711 (2 H, d, J = 8.0 Hz, ArE), 7.29 (2 H, d, J = 8.0 Hz, ArE). Example 1 0 N, N-Diethyl-4- (4-fluorophenyl-hexahydropyridine · 4-ylidene-methyl) -benzidine (Compound 23) was prepared as in Example 1 (Compound 6) The method uses compound 21. ^ NMRGOO MHz, CDCl3) d 1.13 (3 H, br m, CE3CH2 ·), 1.22 (3 H, br, m, CH3CH2-), 2.02 (1 H, br m, NH), 2.30 (4 H, m, hexahydropyridine CE-), 2.90 (4 H, m, hexahydropyridine CH ·), 3.28 (2 H, br m, CILN ·), 3.53 (2 H, br m, CILN ·), 7.04 (2 H, d, J = 8.0 Hz, ArE), 7.11 (2 H, d, J = 8.0 Hz, ArH), 7.25 (2 H, d, J = 8.0 Hz, ArH), 7.30 (2 H, d, J = 8.0 Hz, ArH) 〇 Its HC1 salt: mp 115_120 ° C (H2O-CH2Cl2); IR (KBr) 3337, 2973, 1618, 1431, 1290, 1092 cm_1; Analyze the calculation of C23H27ClN2O.1.0HC1.1.20H2O 値: C, 62.64%; H, 6.95%; N, 6.35%. Found 値: C, 62.53%; H, 6.91%; N, 6.30%. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs D) Preparation Example 1 1 Synthetic Scheme of Compounds Scheme 4

This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 548271 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (36) Example 1 1 Ethyl-4- (phenyl · Preparation of 4- (π-hydroxy-π (4-N-allylhexahydropyridine) Group) -benzyl) -N, N-diethylbenzidine (Compound 24) (81 g) was dissolved in CH2Cl2 (10 ml), and thionyl chloride (2 ml) was used at r · t ·下 处理。 Under processing. The reaction mixture was refluxed for 2 hours and concentrated. The residue was dissolved in ethyl acetate (50 ml), and the resulting solution was washed with NH40H (1N), NH4C1 aqueous solution and brine, and dried over MgS04. The solvent was removed to obtain a crude product, which was purified on a silica gel column and dissolved in MeOH-CH2C12 (1: 9945: 95) to obtain phenyl-α_ (4-N ', N'-diethylaminecarbonylphenyl) -4- Methylene allyl hexahydropyridine (Compound 25; Example 11) (32 mg, 40%); dH (400 MHz, CDCl3) 1.12 (brs, 3H), 1.21 (brs, 3H), 2.43 (m, 4H ), 2.55 (m, 4H), 3.08 (d, J = 6.8 Hz, 2H), 3.25 (brs, 2H), 3.53 (brs, 2H), 5.18 (m, 2H), 5.86 (m, 1H), 7 -12 (ιη, 4H), 7.20 (m, 1H), 7.27 (m, 4H). Its HC1 salt: mp 85-95 ° C (AcOEt-ether-CH2C12); p ma / KBOcuT1 3491, 2971, 1624, 1428, 1289, 1096; Analytical calculation of C26H32N2O.HC1.0.25H2O.0.25CH2Cl22: C , 69.95; H, 7.60; N, 6.21. Found 値: C, 70.00; H, 7.73; N, 6.07. Example 1 2 --- &lt; N, N Diethyl- 4- (4-Gasylphenyl N-N-yl-7T chloro p biyodo-4-acid _ w _ -----! Group) -Preparation of benzylamine (compound 26) The size of this paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) ¾-- (Please read the precautions on the back before filling this page} Order A; 548271 Α7 Β7 Five Description of the invention (37) 0

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs as described in Example 4, using compound 23 (96 mg) and benzyl bromide (43 mg) to obtain N, N-diethyl-4- (4-chlorobenzene -N-benzyl · hexahydropyridine · 4-idene-methyl) -benzidine (110 mg, 93%); 1H-NMR (400 MHz? COCh) δ 1.13 (3 Η? Br m? CH3CH2 -)? 1.23 (3 H, br m, CKsCH2-), 2.37 (4 H, m, hexahydropyridine CH ·), 2.49 (4 H, m, hexahydropyridine CE ·), 3.28 (2 H, br m , CH3CE2N-), 3.53 (4 H, br m, PhCi ^ N and CH3CH2N-), 7.04 (2 H, d, J = 8.0 Hz, ArE), 7.11 (2 H, d, J = 8.0 Hz, ArH) , 7.25 (2 H, d, J = 8.0 Hz, ArH), 7.29 (7 H, m, ArE). Its (CH0HC02H) 2 salt ... mp 110-ll (TC (MeOH); f IR (KBr) 3368, 2977, 1728, 1603, 1433, 1290, 1087 cnT1; Analytical calculation of C34H39aN2O7.1.50H2OO; C, 62.81%; H, 6.51%; N? 4.31%; Measured 6: C, 62.85%; H, 6.17%; N, 4.21%. Example 1 3 N, N_diethyl-1 4-1 [(N-3- Methyl-2 side butyl association) ^ 1-mouse outer dagger <-_-40 -_ This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 548271 A7 B7 V. Description of the invention (38) 4 _Subunit-Methyl) -Benzamidine (Compound 27) Preparation 0

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (27) As described in Example 4, 1-bromo-3-methyl-2_butene was used as the alkylating agent. IR (NaCl film): HC1 salt v = 3432, 2976, 1623, 1434 cm-1; 4 NMR: (base) (CDC13, TMSp: 1.10 ~ 1 · 30 (6Η, br, OCNCH2CE3), 1.64 (3Η , S, = CCEs), 1.73 (3Η, s, = CCE3), 2.40 (4Η, m? NCILCH2), 2.52 (4Η, m, ^ CCEi), 3.0 (2H, d, J- 7.6 Hz? NCHbCH 2C), 3.20 to 3.60 (4H, br, OCNCE2CH3), 5.28 (lH, m, NCH2CE = C), 7.16 to 7.45 (9Η, m, Ar) ppm. Analysis (%): Analysis Pair: C28H36N20.1.8HC1 Calculation 値: C, 69.74; H, 7.90; N, 5.81. Measured 値 ·· C, 69.71; H, 7.48; N, 5.58. &Lt; Example 14 N, N-diethyl- 4-"(1-Cyclohexyl-hexahydropyridine-4-ylidene) -phenyl-methyl1-phenylhydrazine (Compound 28) Preparation of this paper applies Chinese National Standard (CNS) A4 specification (210X 297 (Mm) 548271 A7 B7 V. Description of the invention (39)

hr

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (28)

Compound 6 (100 mg, 0.29 mmol), cyclohexanone (36 µl, 0.35 mmol) and Ti (OPr-i) 4 (0.17 ml, 0.58 mmol) were treated with ultrasound After 1 hour, it was stirred at RT and N2 overnight. The mixture was diluted with ethanol (5 mL), and then NaBH4 (33 mg, 87 mmol) was added. The resulting mixture was stirred at rt for 12 hours, and the reaction was stopped by adding 2N NH3.Η20, and the mixture was filtered through celite. The filtrate was extracted several times with ethyl acetate, and the combined organic phases were washed with water and brine, dried over Na2S04, concentrated under vacuum and purified by MPLC (0: 100 to 100: 0 EtOAc: heptane, dissolved on silica gel (60)) The title compound (24 mg, 20%) was obtained in mp (HCl salt): 105-109 ° C IR (HC1 salt, film): 1: 3394 (NH), 1620 (CO ^ Et2) cm-1. 4 NMR (free state amine, 400 MHz, CDC13) d: 1.00 to 1.25 (17Η, m, NCHCH.CH.CHoCHoC% 2xCH, and CH (CH) CC), 1.60 (1H? M? £ H (CH) OC), 1.75 (1Η, m, £ H (CH) OC), 1 · 80 (1Η, m, CH £ CH) C = 42-This paper size applies to China National Standard (CNS) A4 (210X 297mm) 548271 A7 B7 5. Description of the invention (4〇) Please read the notes on the back before filling this page C), 2.30 (3H, m, NCHZ and NCH)? 2.60 (2H, m, NCH〇) V 3.20 (2Η, bs, NCHoCHA 3.50 (2H, bs, N £ E2CH3), 7.00-7.30 (9Η, m, At). 13C NMR (free state amine, 100 MHz, CDC13) d: 12.7, 14.1, 25.9, 28.7, 32.0, 39.1, 43.2, 50.7, 50.8, 63.6, 126.0, 126.3, 127.9, 129.7, 129.8, 134.7, 134.9, 136.9, 142.0, 143.4, 171.2. Elemental analysis pair: Calculation of C29H4GN2〇a2 : C, 69.17; H, 8.01; N, 5.56. Measured 値: C, 69.17; H, 7.82; N, 5.18. Example 1 5 N, N-Diethyl-4-[(N-butyl) -benzene Of Benzyl-ττ Ammonia Exo-4-Subunit-Methyl] · Benzamidine (Compound 29)

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs As described in Example 4, 1-iodobutane was used as the alkylating agent. IR (NaCl film): (HC1 salt) ι / = 3430, 2967, 2499, 1622, 1433 cm -43 This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 548271 A7 B7 V. Description of the invention Ui ) NMR (CDC13, TMS) (ί: 0.92 (3H, t, J = 7.2Hz, CH, CHA 1.20-ΐ · 2έ (6Η, br, 〇cnch2CH3)? 1.32 (2H? M, CH2CH3), 1.53 (2H? M, CH2CH2CH2), 2.42 (6H? M? NCH2)? 2.55 (4Η, m, = CCH2), 3.20 ~ 3 · 60 (4Η, br, OCNCILCHs), 7.10-7.31 (9H, m , Al) ppm 〇 Analysis: (%) Analytical pair: Calculation of C27H36N20 · HQ · 0.4CH2C12 · 0.4 · 2Ο 値: C, 68.24; H, 8.07; N, 5.81. Measured 値: C, 68.24; H, 8.12; N, 5.89. Example 1 6 N, N-Diethyl-4-[(N-4 -methoxybenzyl) _phenylhexahydropyridin-4-ylidene-methyl) -phenylhydrazine ( Preparation of compound 30).

The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed the method described in Example 4 using compound 6 (174 mg) and 4-methoxyfluorenyl chloride (78 mg) to obtain 1! ^-Diethyl-4 [( ^^-4-Methoxybenzyl) -phenyl-hexahydropyridine-4-ylidene-methyl] • benzidine (160 mg, 68%). ^ -NMRQOO MHz, CDCl3) d: 1.11 ( 3H, br, CE3CH2N_), 1.20 (3 H, br, CEbCH2N ·), 2.38 (4H, m, CCH ^ C), 2.46 (4 H, m, NCE2 ·), -44-This paper standard applies to Chinese national standards (CNS) A4 specification (21OX297 mm) 548271 A7 B7 V. Description of the invention (42) 3.26 (2Η, m, NCH ^), 3.47 (2H, s, CI ^ N-), 3.49 (2Η, br, CH3CE2N ·), 3.77 (3Η, s, OCE3), 6.83 (2Η, d, J = 8.0 Hz, ArH), 7.05 · 7 · 30 (11 H, m,

ArH) 〇 Its HC1 salt: mp 100-110 ° C (CH2C12); IR (KBr) 3425, 2974, 1618, 1515, 1434, 1255 cm · 1; Analytical calculation of C31H36N202.1.0HC1 0.35CH2C1212: C, 70.41%; H, 7.11%; N, 5.24%; Found 値: C, 70.46%; H, 7.10%; N, 5.21%. Example 1 7-—Ethyl-4 · "(N-2,4 -monofluorophenylphenylhexaaminopyridine-4-pyridine-4-methylene) -benzylamine (compound 3 1) 〇

The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed the method described in Example 4, using compound 6 (1744 g) and ", 2,4-trichlorotoluene (98 mg) to obtain Ν, Ν_diethyl -4 [(N_2,4-dichlorobenzyl) -phenyl-hexahydropyridine-4-ylidene-methyl] -benzidine (206 mg, 81%). ____-45-Applicable towels for this paper size Guanjia County (CNS) Α4 specifications (21〇χ 297 mm 1-548271 A7 B7 V. Description of the invention (43) Please read the notes on the back before filling in this page 4 NMR (400 MHz, CDCl3) d 1.12 ( 3H, br, CE3CH2N-), 1.21 (3Η, br, CE3CH2N-), 2.39 (4Η, m, CCH ^ C), 2.52 (4H, m, NCIL-), 3.28 (2H, m, NCH ^), 3.53 (2H, br, CH3CE2N ·), 3.57 (2H, m, NCIL surface), 7.05-7.48 (12 H, m, ArH) 0 its HC1 salt: mp 95-110 ° C (CH2Cl2); IR (KBr) 3408, 2976, 1620, 1472, 1436, 1288, 1101 cm 1; Analytical calculation of C30H32N2OC12.1.0HC1 0.30CH2C1212: C, 63.91%; H, 5.95%; N, 4.92%; Measured 値: C , 63.81%; H, 6.03%; N, 4.84%. Example 1 8 N, N-diethyl-4- 丨 (1-methyl-hexapyridine-4-ylidene) -phenyl-methyl Preparation of benzamidine (Compound 32)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of N, N-diethyl-4-[(hexahydropyridine-4-ylidene) · phenyl · methyl] -phenylhydrazine (0.34 g, 1.0 mmol) Ear) dissolved in acetonitrile (5 ml). MK2CO3 (0.14 46-This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 548271 A7 _________ B7 V. Description of the invention (44) g, 1.0 millimolar) and methyl iodide (63 Microliters, 1.0 millimolar) and stirred at 25 ° C. After 30 minutes, the reaction mixture was evaporated and poured on gelatin for purification by chromatography. Using 0 to 10% ~ ^ 011 (10./114011) (in (1120: 12)) to obtain 48 mg of the final product (28 % Of converted starting material), which was converted to the hydrochloride salt by treatment with HC1 in ether.

Mp: 1 100 ° C (dec.). IR (KBr) (cm-1): 2361, 1695, 1487, 1289. MS (free state amine): 362, 318, 219, 189, 165, 144. iH NMR (amine, CDCl3) cy = 11 (m, 6H, amine-Me), 2.40 (s, 3H, MeN), 2.49, 2.60 (2m, 8H, hexahydropigment-H), 3.40 (m, 4H, amine _ (: out), 7.08-7.34 (m, 9H, Ar-H). C24H3ON20xO.l H20 χ3.1 HC1, shall: C: 60.39, H: 7.03, N: 5.87. Found Rhenium: C: 60.43, H: 6.84, N: 5.45. Example 1 9 N, N -diethyl-4-[(N -third butoxycarbonyl-hexahydro p-pyridian-4 -yl) -8 -p-quinolate / ^ Aminobenzene I-methyl-1-Hydroxyl_ printed by the Central Consumers Bureau of the Ministry of Economic Affairs

2 B

\ — / 3 (3 47 This paper size applies to Chinese National Standards (CNS) A4 specifications (210X 297 mm) 5. Description of the invention (45) on 4-sulfo-N, N_diethylphenylamine (1.52 g , 5.0 mmol) and 8-bromoquinoline (1.0 g) in anhydrous THF (30 ml), add n-butyllithium (7.0 ml, 2.5 M, 17.5 mmol) at -78 ° C After 10 minutes, N-tert-isobutoxycarbonyl ethyl (2) (0.77 g, 3.0 mmol) (in 5 ml of THF) was added dropwise. The reaction mixture was warmed to C, and then NH4C1 The reaction was quenched with aqueous solution and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with brine and dried over Mg S 04. The solvent was removed to give the crude product, which was purified on a Meggel column and MeOH- CH2Cl2 (2:98) dissociates to obtain MTL 0599 (145 mg, 9%): mp 100-105 ° C; IR (NaCl) 2971, 1686, 1625, 1426, 1167 cm-1; Analytical calculation of C31H39N304.0.20H20値: C, 71.43%; H, 7.62%. Actual measurement printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 値: C, 71.50%; H, 7.75%; b-NMRGOO MHz, CDCl3) d 1.07 (3 H, br, CEsCH2N-), 1.19 (3Η, br, CH ^ CH 2N-), 1.24 (1 H, m, hexahydropyridine CH ·), 1.43 (9Η, s, CHsC), 1,65 (1 H, m, hexahydropyridine CE_), 1.89 (2 H, m , Hexahydropyridine CE_), 2.52 (1 H, m, hexahydropyridine CH-), 2.64 (1Η, br, hexahydropyridine Cii_), 2.78 (1 H, br, hexahydropyridine CH_), 3.22 ( 2 H, br, CH3CE2N-), 3.49 (2 H, br, CHsCiLN-), 4.16 (2 H, br, hexahydropyridine CE ·), 7.24 (2 H, d, J = 8.0 Hz, ArH), 7.35 (1 H, dd, J = 8.0, 4.4 Hz, Arii), 7.55 (2 H d, J = 8.0 Hz, ArH), 7.58 (1 H d, J = 8.0 Hz, ArH), 7.71 (1 H , D, J = 8.0 Hz, Arii), 7.80 (1 H, d, J = 8.9 Hz, ArH), 8.14 (1 H, d, J = 8.0 Hz, ArH), 8.69 (1 H, m, ArH) , 9.80 (1H, s, OH). Example 20 Ν, Ν diethyl _ 4 _ (8-sturdy forest-based hexachloroacetic acid _ 4 _ subunit methyl)-Ben 6¾ This paper size applies to China National Standard (CNS) A4 (210X297 mm) ) 548271 A7

V. Description of the Invention (46) Amine (Compound 〇

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

I Η (34) A mixture of the compound of Example 19 (45 mg), trifluoroacetic acid (10 ml) and trifluoromethylene acid (1 liter) was refluxed for 8 hours, and then concentrated. The residue is soluble

AcOEt (50 ml). The resulting solution was washed with 1N NaOH solution, NH4C1 aqueous solution and brine, and dried over Na2SO4. The solvent was removed to obtain a crude product, which was purified by a Shixi gel column and dissolved with NH4OH + (1N) _MeOH-CH2Cl2 (2.5: 17.5: 80) to obtain N, N_diethyl-4- (8-quinolinyl- Hexahydropyridin-4-ylidene-methyl) -benzidine (29 mg, 84%); iH-NMR (400 MHz, CDC13) (J 1.07 (3 H, br m, CE3CH2 ·), 1.20 (3 H, br m, CHsCH2 ·), 2.00 (2 H, m, hexahydropyridine CH ·), 2.46 (1H, s, NH), 2.52 (2 H, m, hexahydropyridine Cjl ·), 2.75 (1 H , M, hexahydropyridine Cii ·), 2.92 (2Η, m, hexahydropyridine CH ·), 3.05 (1 H, m, hexahydropyridine CE-), 3.22 (2 H, m, CiLN ·), 3.49 (2 H, m, CILN-), 7.23 (2 H, m, ArH), 7.32 (2 H, one 49 _ This paper size applies to China National Standard (CNS) A4 specifications (2! 〇 &gt; &lt; 297 (Mm) 548271 A7 B7 V. Description of the invention (47) m, ArH), 7.36 (1 H, m, ArE), 7.49 (2 H, m, Ar pull), 7.72 (1 H, dd, J = 6.4, 3.2 Hz, ArH), 8.11 (1 H, dd, J = 8.4, 1.6 Hz, ArH), 8.91 (1H, dd, J = 4.0, 1.6 Hz, Arii) 0, its HC1 salt: mp> 170 ° C ( Dec.); IR (KBr) 3410, 2973, 1614, 1551, 1436, 1284 cm-1; Analysis of C26H29N30 0 HC1. 0.50 Calculated 値 for CH2C12 · 0.75 H20; c 60.23%; H, 6.39%; Measured 値: C, 60.27%; H, 6.42%. Example 2 1 N, N 雠 Diethyl second butoxy M · Ττ Ammonia ratio &lt; -4 -yl) -3 oxybenzene-hydroxymethyl) -benzidine (compound 3 5) Please read the back

Page I Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 〇

ΌΜθ As in Example 19, 3-bromoanisole was used to obtain the standard reed compound (226 g, 23%): mp 95-103 ° C; IR (NaCl) 3422, 2973, 1684, 1614, 1429, 1289 cnT1 ; -50-This paper size applies to China National Standard (CNS) A4 (210X297mm) 548271 A7 B7 1 ^ ----------------------- ----------- --............................ 丨 V. Invention Description (48) Analysis Calculated for C29H4ON205.0, 60H20 値 'C, 68.64%; H, 8.18%; N, 5.52%. Measured 値: C, 68.66%; Η, 7.98%; N, 5.64%; iH-NMRGOO MHz, CDC13) ^ 1.0 (3 H, br, CE3CH2N-), 1.19 (3 H, br, CE3CH2N- ), 1.31 (4 H, m, hexahydropyridine CK-), 1.41 (9 Η, s, CH3C), 2.46 (1 H, m, hexahydropyridine CH-), 2.64 (2 H, br, hexahydro Pyridine CE_), 3.22 (2 H, br, CH3CE2N-), 3.49 (2 H, br, CH3CE2N-), 3.65 (1 H, soe), 3.72 (3 H, s, OCEs), 4.06 (2 H, br, hexahydroton lake CH-), 6.69 (1 H, m, ArH), 7.01 (1Η, d, J = 7.6 Hz, ArH), 7.08 (1 H s , Arii), 7.17 (1 H, d, J = 8.0 Hz, ArH), 7.21 (2 H, d, J = 8.0 Hz, ArH), 7.48 (2 H, d, J = 8.0 Hz, ArH). Example 22 Preparation of N, N -diethyl 4-(3 -methoxyphenyl-ττfeng p ratio -4-subunit -toluene) -phenylhydrazine (compound 36)

The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed the method described in Example 1, using the compound of Example 21 (1 ο 0 mg) to obtain N, N · diethyl-4_ (3-methoxyphenyl-hexahydro Pyridine-4-ylidene-methyl) -phenylhydrazone The paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297 mm) 548271 A7 B7 V. Description of the invention (49) Amine (75 mg, 98%): ^ -NMRGOO MHz, CDC13H 1.12 (3 H, br, CE3CH2N-), 1.23 (3 H, br, CH3CH2N-), 2.34 (4 H, m, hexahydropyridine CH-), 2.91 (4Η, br, Hexahydropyridine C £ l ·), 3.17 (1 H, s, NH), 3.27 (2 H, br, CH3CH2N-), 3.52 (2 H, br, CH3CE2N-), 3.76 (3 H, s, OCEs) , 6.64 (1 H, s ArE), 6.70 (1 H, d, J = 8.0 Hz, Aril), 6.76 (1 H, d, J = 7.6 Hz, Arii), 7.15 (2 H, d, J) 8.0 Hz, Aril), 7.22 (1 H, m, ArE), 7 29 (2 H, d, J = 8.0 Hz, ArH). Its HC1 salt: mp> 90 ° C (Dec); IR (NaCl) 2970, 1621, 1430, 1287cm-1; Analytical calculation of C24H3GN2O2.HCL1.70H2OO; C, 64.69%; H, 7.78%; N, 6.29%; actual fluorene: C, 64.82%; H, 7.60%; N, 6.08%. Example 23 N, N -diethyl-4 _ [(N-fluorenyl) -3_methoxybenzyl-hexahydroπ Preparation of Biyodo_4 -Subunit-methyl] benzidine (Compound 37) Please read the notes on the back before filling in this page

548271 A7 B7 V. Description of the invention (50) As in Example 4, the compound of Example 22 (38 mg) was used to obtain N, N_diethyl-4-[(N-fluorenyl) -3_methoxyphenyl -Hexaline ρ Biyodo-4 · subunit-methyl] -benzidine (46 mg, 98%): i-NMRGOO MHz, CDCl3) d 1.12 (3 H, br5 CEsCH2N ·), 1.25 (3 H, br, CHsCH2N_), 2.38 (4 H, m, hexahydropyridine CH ·), 2.48 (4Η, br, hexahydropyridine CH-), 3.27 (2 H, br, CH3CH2N-), 3.52 (2 H, s, PhCH2N), 3.53 (2 H, br, CH3CE2N-), 3.75 (3 H, s OCEs), 6.65 (1H, s, ArH), 6.69 (1 H, d, J 8.0 Hz, Arii), 6.74 (1 H, d, J = 7.6 Hz, ArH), 7.13 (2 H, d, J = 8.0 Hz, ArE), 7. 13-7.32 (8 H, m, ArH). Its HC1 salt: mp l00-110 ° C (CH2Cl2); IR (NaCl) 3421, 2972, 1619, 1430, 1287cm_1; Analyze the calculation of C31H36N2O2.HC1.0.40CH2a2; C, 69.96%; H, 7.07%; N? 5.20%; Actual 値 ·· C, 69.94%; H, 7.06%; N, 5.15%. Example 24 N, N-diethyl-4- [(N_thirdbutoxycarbonyl-hexahydropyridin-4-yl)- 3 · Preparation of fluorophenyl-hydroxymethyl] -benzidine (compound 38) Attention. Item Refan Page Order Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs + L Ε

F 8) 53 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 × 297 mm) 548271 A7 B7 V. Description of the invention (M) As in Example 19, the title compound (257 mg, 27%): ^ -NMRC ^ O MHz, CDCls) ^ 1.03 (3 H? Br9 CH3CH2N-), 1.15 (3 H, br, CH3CH2N-), 1.19-1.29 (4 H, m, hexahydropyridine CH-) , 1.35 (9Η, s, CE3C), 2.39 (1 H, m, hexahydropyridine CH-), 2.59 (2 H, br, hexahydropyridine Cii-), 3.17 (2 H, br, CH3CE2N-) , 3.28 (1 H, s 0ϋ), 3.45 (2Η, br, CH3CILN ·), 4.02 (2H, br, hexahydropyridine CH--), 6.80 (1H, m, ArE), 7.15 (3 H , M, ArH), 7.18 (2 H, d, J = 8.0 Hz, ArH), 7.39 (2 H, d, J = 8.0 Hz Aril). Example 25 N, N -diethyl-4-( Preparation of 3-rhamnylbenzene; -hexamidine p-pyridine-4 -methylene-methyl] -aspartamine (compound 39).

The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed the method as in Example 20, using the compound of Example 24 (165 mg) to obtain N, N_diethyl_4- (3-Gaphenyl-Fengwaibiao-4 _Subunit-methyl] -benzamine (108 mg, 87%) h-NMRGOO MHz, CDCl3) d 1.08 (3 H, br, CE3CH2N-), 1.19 (3 This paper size applies to Chinese National Standards (CNS) A4 specification (210X297 mm) 548271 A7 __ B7 V. Description of the invention (52) H, br, CHsCHbN-), 2.09 (1 H, s, NE), 2.25 (4 H, m, hexahydropyridine CH-), 2.84 (4Η, br, hexahydropyridine CH-), 3.23 (2 H, br, CHsCILN ·), 3.47 (2 H, br, CH3CE2N-), 6.74 (1 H, m, ArE), 6.86 (2 H, m Arii), 7.06 (2Η, d, J = 8.0 Hz, ArH), 7.18 (1 H, m, ArH), 7.24 (2 H, d, J = 8.0 Hz, ArH). Its HC1 salt: mp> 70 ° C (Dec.); IR (NaCl) 2978,1605,1478,1432,1290cm1; Analytical calculation of C23H27N2OF.HC1.0.25CH2Cl2.1.50H2O 値; C, 61.89%; H, 7.04%; N, 6.21%; Actual 値: C, 61.97%; H, 6.95%; N, 6.22% · E) Preparation of the compound of Example 26, a schematic illustration of the preparation of the compound of Example 6, as shown in Figure 5 below. Display method: Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5 5 Shi ’s Zhang scale is applicable to Chinese National Standard (CNS) A4 specifications (21GX297 mm) 548271 A7 B7 V. Description of the invention (53 Figure 5, ja

NH〇 Ac20 / CH2CL… CH JTT㈣

1) NaH, 0 ° C, THF 2) n-BuLi, -78 ° C 3)

Li Boc 〇

N I Boc】 γ〇Η3 (41) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

NaOH Me! Bu4NHS〇4

(43) CH. I 3 N CHT 〇 3 TFA CH2C! 2

CH. I 3 N… CH.

T —_ This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 548271 A7 ______B7 V. Description of the invention (M) (i) 4'-iodine · acetanilide (Compound 40) was prepared at 4 -A solution of iodine · aniline (15 g, 69 mmol) in anhydrous CH2C12 (100 ml), acetic anhydride (14.09 g, 138 mmol) was added at rt, and the reaction mixture was stirred for another 2 hours. The gray precipitate formed in the reaction was filtered, washed with ether and collected. The mother liquor was concentrated to dryness, and Ac OEt was added. The resulting precipitate was filtered, washed with ether and combined with the previous solid to form the desired product (15.95 g, 88.7%). NMR (CDCl3) d2.19 (3H, s COCEs), 7.2 (1Η, s, br, · Nϋ), 7.23 (2H, m, Ar), 7.61 (2Η, m, Ar) (ii) 4 -(4 · Ethylaminophenylbenzyl) -N-Third-Butoxycarbonyl Hexahydropyridine (Compound 41) Printed on 4. Iodine-Ethylaniline (11.7 G, 45 mmol) in anhydrous THF (200 ml), and under Ot: NaH (1.62 g, 67.5 mmol) was added, and the reaction mixture was stirred for 30 minutes while the temperature was allowed to reach room temperature, then slowly Add -BuLi (1.6M, in Geng face, 54 mmol) at -78 ° C. The mixture was stirred for 15 minutes, and N-tert-butoxycarbonyl-N'-methyl-N, -methoxy-isopiperidinamide (6.15 g, 30 mmol) was added dropwise via a syringe. 10 ml of THF). The reaction mixture was warmed to r.t. and the reaction was stopped with NN4C1 aqueous solution, and extracted with ethyl acetate (2 X 100 ml). The organic layer was washed with a saturated NH4C1 aqueous solution, brine, dried over MgS04, and concentrated to obtain a crude product, which was then subjected to column chromatography by Shixi gel column] ^ 60〇11-(^ 112〇12 (〇: 100 ~ 5: 95), and the desired product was obtained (9.02 g, 87%). NMR (CDCl3) d: 1.47 (9H, s, (CH3) 3), 1.6 · 1.8 4Η, m, hexahydropyridine), 2.21 (3Η, s, COCH3), 2.9 (2Η, m, hexahydro-Edo), 3.37 (1Η, m, COCH ·), 4.15 ( 2Η, m, hexahydro p ratio lake), 7.64 (2Η, m, Ar), 7.86 (1H, s, br, -CONii), this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) ) 548271 A7 ____B7 V. Description of the invention (55) 7.91 (2Η, m, Ar) (iii) g α-Hydroxy_ α (4_Nthironyloxycarbonylhexahydropyridyl) _3_ 氪 benzyl) acetamidine Amine (Compound 42)! ^ The method described for the preparation of compound 4 'but using 3-fluoro-iodobenzobromofluorene' gave the title compound (93%). 1h NMR: (DMSO-D6) J: 1 · 2-1 · 3 (4Η, in, hexahydropyridine) ,! 37 (9H, s, (CH3) 3), 2.0 (3Η, s, COCH3), 2.65 (3Η, br, hexahydropyridine), 3.95 (2Η, m, p-Hydrogen) , 6.98 (1Η, m, Ar), 7.21-7 · 50 (7Η, m, Ar), 9.85 (1Η, s, OC · NH) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy (iv) &amp;,.,. Methyl · 4- (α-Hydroxy-"(4-- · Third-butoxycarbonylhexahydropyridylfluoromethyl) acetanilide (Compound 43) was prepared in 2M NaOH Aqueous solution (10 ml) was added with tetrabutylammonium hydrogen sulfate (135 g, 3.97 mmol), followed by 4_ (from -hydroxy third butoxycarbonylhexahydropyridyl) -3-fluorofluorenyl) acetamidine A solution of aniline (825 mg, 1.86 mmol) and methylamine (769 mg, 5.4 mmol) in 10 ml of ch2C12. The reaction mixture was refluxed for an additional hour, cooled to r.t., and the CH2C12 layer was collected and evaporated. Ethyl acetate was added to ~ 1 mL, and the precipitate was filtered off. The organic phase was washed with brine, dried over MgSCU, and concentrated to give a solid, which was purified by MPLC with MeOH-CH2C12 (5:95) to give the pure title compound (770 mg , 93%). 4 NMR (CDCl3) d: 1.2 · 1.5 (4Η, m, hexahydropyridine), 1.42 (9H, s, (CH3) 3X 1.83 (3H? S? COCHsX 2.52 (1H, m? -CH-C-OH), 2.70 (2H? Hexahydropyridine), 2.86 (1Η, s, br, _OH), 3.21 (3Η, s , NCHa), 4 · 15 (2Η, s, br, hexahydropyridine), 6.90 (1H, m, Ar), 7.12-7 · 60 (7Η, m, Ar) Example 26 This paper scale applies Chinese national standards ( CNS) A4 specification (210X297 mm) 548271 A7 B7 N-methyl-4- (3-fluorophenyl-hexahydro leaf I: Yodo-4_ylidenemethyl) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Aniline acetate (Compound 44) was prepared from N-methylhydroxy · π (4-N -third butoxycarbonylhexahydropyridyl) -3-fluorobenzyl) aniline acetate (300 mg, 0.657 mmol) The solution in anhydrous CH2C12 (5 ml) was added with trifluoroacetic acid (5.0 ml) at rt. The reaction mixture was refluxed for 4 hours and concentrated. The residue was dissolved in AcOEt (50 ml). The resulting solution was 2N NaOH aqueous solution, NH4C1 The solution was washed with aqueous solution and brine and dried on MgSCU. The solvent was removed to obtain the crude product, which was purified by MPLC and dissolved in MeOH-CH2Cl2-NH4OH (5: 95: 1) to obtain the pure product (176 mg, 79%). Mp235 ~ 237〇C dec.IR (NaCl film) :( HC1 salt) i / (max. ) = 2961, 2722, 2480, 1658, 1608, 1580, 1507, 1429, 1381CHT1. ^ -NMRCCDCls) d: 1.89 (3H, s, COCEs), 1.95 (1Η, s, -NH), 2.32 (4Η, m, hexahydrogenated lake), 2.92 (4Η, m, six Hydrogen lake), 3.26 (3η, s, N-CEs), 6.81-7 · 28 (8Η, m, Ar) 13C NMR (CDCl3) d: 22.4 · 33.2, 33.3, 37.0, 48 · 3 , 113.3 (m, CF), 116.5 (m, CF), 125.4, 126.6, 129.5, 129.6, 130.9, 133.7, 137.7, 141.2, 142.8, 144.2, 161.3, 163.8, 170.4 ·. Analysis: (%) Analysis 値 AHnNJO · Calculation of HC1: c, 67.28; H, 6.45; N, 7.47. Found 値: C, 66 · 88; H, 6.44; N, 7.16. F) Preparation Example 7 Synthesis of Compound 7 The compound of Example 27 was prepared according to the method shown in Figure 6 below. 59-The M's scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm). Please read the back side of the paper first, and then order it in m% Ψ 548271 A7 B7 V. Description of the invention (57 Figure 6)

0

b〇c9〇 / dcm N Ν Η 1 (45) BOC (46) 〇

1. LDA / THF 2. 0 BOC (46)

Boc (49) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

〇 Bry / DCM

Br NaOH / MeOH

OH

Ar-B (〇H) 2 / Pd0 / Na2C〇:

NIH (52) (54) Example 27. (53) -60-

This paper size applies to China National Standard (CNS) A4 (210X297 mm) 548271

V. Description of the invention (%) (i) Preparation of N-third butane carbonyl-4-hexahydropyridone (compound 46) Compound 45 (50 g, 0.325 mole) and di-tert-butyl dicarbonate (71 g '0.325 mol) in 300 ml of CH2C12, stirred at ot while adding triethylamine (133 g, 1.32 mol) dropwise, the mixture was allowed to warm to room temperature and stirred for 12 hours. The solvent was evaporated and the crude product was partitioned between water (400 ml) and acetic acid (400 ml). The aqueous phase was washed with another portion of ether (400 ml). The combined ethers were washed with water (400 mL) and brine (400 mL), and dried over MgS04. Removal of the solvent gave compound 46 as a pale yellow solid (5 5.3 g, 8 5%) 〇dH (400 MHz, CDC13) 1.50 (s, 9H), 2.45 (t, 4H, J = 6.1 Hz), 3.72 (t , 4H, J 2 6.1 Hz). (ii) Boro- (4-methoxycarboxy-benzylidene) · hexahydrop-pyridine-1-leptin tert-butyl vinegar (compound 49) methyl 4- (bromomethyl) benzoate ( Compound 47) (11.2 g, 49 mmol) was dissolved in 25 ml of trimethyl phosphite and refluxed under n2 for 5 hours. Distillation with toluene to remove excess trimethyl phosphite gave crude 4- (dimethoxy-phosphoniummethyl) donggujia @ Mi (Compound 48). Printed by the Central Bureau of Standards of the Ministry of Economy—Industrial and Consumer Cooperatives ΘΗ (400 MHz, CDCl3) 3.20 (d, 2H, J = 22 Hz), 3.68 (d, 3H, 10.8 Hz), 3.78 (d, 3H, 11.2 Hz) 3.91 (s, 3H), 7.38 (m, 2H), 8.00 (d, 2H, J = 8 Hz). The crude product (Compound 48) was dissolved in anhydrous THF (200 mL) under N2 and cooled to -78 ° C. Lithium diisopropylamide (32.'ml, 1.5M (in hexane), 49 mmol) was added dropwise. The solution was allowed to warm to r.t. A solution of compound 46 (9.76 g. 49 mmol (in 100 ml of anhydrous THF)) was added dropwise to the reaction, and stirred at% for 12 hours. Add water (300 ml) and ethyl acetate (300 ml) ____- 61 -_____ This paper size applies to China National Standard (CNS) A4 (210X297 mm) 548271 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Invention description (59) to the reaction mixture and extraction. The aqueous phase was washed with ethyl acetate (2 X 300 ml). The combined ethyl acetate was dried over MgSO and evaporated to give a crude product, which was purified by silica gel chromatography (0.33% ethyl acetate (in hexane)) to give compound 49 as a white solid ( 5.64 g, 35%). dH (400 MHz, CDC13) 1.44 (s, 1H), 2.31 (t, J = 5.5 Hz, 2H), 2.42 (t, J = 5.5 Hz, 2H), 3.37 (t, J = 5.5 Hz, 2H), 3.48 (t, J = 5.5 Hz, 2H), 3.87 (s, 3H), 6.33 (s, 1H), 7.20 (d, J = 6.7 Hz, 2H), 7.94 (d, J = 6.7 Hz, 2H). Xi c-13 (CDC13) 28.3, 29.2, 36.19, 51.9, 123.7, 127.8, 128 · 7, 129.4, 140.5, 142.1, 154.6, 166.8 ppm. Vmax (NaCl) cm_1 3424, 2974, 2855, 1718, 1688, 1606 , 1427, 1362, 1276 〇 Analyze the calculation of Q9H25NO4; C 68.86%, H 7.60%, N 4.23%; Found: C 69.1%, H 7.69%, N 4.25%. (iii) Preparation of 4-bromo-4- [bromo- (4-methoxycarbonyl-benzyl) -methylη-hexahydropyridine-! carboxylic acid third butyl ester (compound 50) in compound 49 (5.2 g, 16 millimoles) in anhydrous CH2C12 (200 ml), and grain solution 'plus K 2 C 0 3 (1.0 g). A solution of brook (2.9 g, 18 millimoles in 30 ml of DCM) was added dropwise at 0 C, and stirred at r.t. for 1.5 hours. K: 2CO3 was removed by filtration, and the solvent was evaporated to dryness. The crude product was dissolved in ethyl acetate (200 mL), washed with water (200 mL), 0.5M HC1 (200 mL), and brine (200 mL), dried over MgS04, and the solvent was evaporated to obtain the crude product. Recrystallization from methanol gave compound 50 as a white solid (6.07 g, 78%). d H (400 MHz, CDC13) 1.28 (s, 9H), 1.75 (m, 2H), 1.90 (m, 2H), 2.1 (m, 4H), 3.08 (br, 4H), 3.90 (s, 3H), 4.08 (br, 4H), 5.14 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H). d c_13 (400 MHz, this paper size applies to Chinese National Standard (CNS) A4 specifications (21OX297)) (Please read the precautions on the back before filling out this page) ¾ Clothing-548271 A7 B7 Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed 5. Description of the invention (60) CDC13) 28.3, 36.6, 38.3, 40.3, 52.1, 63.2, 72.9, 129.0, 130 · 3, 130.4, 141.9, 154.4, 166.3 ppm. I / mdNaCDcnT1 3425, 2969, 1725, 1669, 1426, 1365, 1279, 1243. Analysis pair: C19H25Br2N04 calculation 値; V 46.6%; Η 5.13%, · N 2.85%; measured 实: 46 · 64%, Η 5.16%, Ν 2.89%. (iv) Preparation of 4- "bromo- (4-carboxyphenyl) -methylene 1-hexahydropyridine-1-carboxylic acid third butyl ester (Compound 51) in Compound 50 (5.4 g, 11 mmol) ) In methanol (300 ml), 2.0 M NaOH (100 ml) was added at 40 ° C. The reaction was stirred at 40 ° C for 3 hours. The crude salt solid was isolated by filtration and dried overnight under a vacuum. The dried salt was dissolved in 40% acetonitrile / water and the pH was adjusted to 2 with concentrated HC1. The desired product (7) (3.8 g, 87%) was isolated as a white powder by filtration. "(400 MHz, CDC13) 1.45 (s, 9H), 2.22 (dd, J = 5.5 Ηζ, 6.1 Hz, 2H), 2.64 (dd, J = 5.5 Hz, 6.1 Hz, 2H), 3.34 (dd, J = 5.5 Hz, 6.1 Hz, 2H), 3.54 (dd, J = 5.5 Hz, 6.1 Hz, 2H), 7.35 (d, J = 6.7 Hz, 2H), 8.08 (d, J = 6.7 Hz, 2H). d c_13 (400 MHz, CDC13) 28.3, 31.5, 34.2, 44.0, 115.3, 128.7, 129.4, 130.2, 137.7, 145.2, 154.6, 170.3. Analysis pair: C18H22BrN04 calculation04; C 54.56%, H 5.60%, N 3 · 53%; Found 値: C 54.66%, H 5.68%, N 3.59%. (V) 4- 丨 Bromo- (4-diethylamine formamidine-phenyl) -methylene 1-hexahydropyridine- 1-Preparation of tert-butyl carboxylic acid (compound 5 2) — \ A solution of compound 51 (1.0 g, 2.5 mmol) in anhydrous (: 112 (: 12 (10 ml)) at -20 ° Add isobutyl chloroformate (450 mg, 3.3 mmol) at C. After 20 minutes, add diethylamine (4 ml) at -20 ° C to bring the reaction temperature to ___- 63 -_____ Paper size Applicable to China National Standard (CNS) A4 specification (210'〆297 mm) (Please read the notes on the back before filling out this page} r _ order. 548271 A7 ____ B7 V. Description of the invention (61) r · t ·. After 1 · 5 hours, the solvent was evaporated and the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate was washed with water and brine, dried over Mg S04, and removed by evaporation. The crude product Purified by silica gel chromatography (0.60% ethyl acetate in heptane) to obtain the product (compound 52) as a white needle (800 mg, 73%). Βh (400 MHz, CDCl3) 1.13 (bi :, 3H), 1.22 (br, 3H), 1.44 (s, 9H), 2.22 (t, J = 5.5 Hz, 2H), 2.62 (t, J = 5.5 Hz, 2H), 3.31 (t, J = 5.5 Hz, 2H), 3.52 (t, J = 5.5 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H). Dc-i3 (400 MHz, CDCl3) 12.71 · 14.13, 28 · 3, 31 · 5, 34 · 2, 39 · 1, 43 · 2, 79.7, 115.9, 126.3, 129.3, 136 · 8, 137 · 1, 140.6, 154.6, 170.5. Analysis pair: Calculated C22H31BrN203; C 58.3%, C 6.92%, N 6.21%; Measured C: C 58.62%, 6.89%, 6.21%. Example 27 Preparation of N-monoethyl_4- "hexahydrop-pyridine-4-subunit (3-fluorotolylmethanine to acid amine (compound 54, Ar = 3-trifluoromethylbenzyl)) (One boat ancient method) The reaction of the sozaki coupling of compound 52 with various boranes and subsequent deprotection are performed in small scale in parallel, and the reaction and liquid-liquid extraction are performed in a 25 X 1 50 mm culture tube. Typical reaction A summary of the experimental day book is as follows. Printed on compound 52 (25¾ g, 57 μmol) and palladium (triphenylphosphine) palladium (〇) (5 mg, 4.3 μmol) by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. ) In xylene (degassed, 0.05 ml) and add 3-trifluorophenylborane (28.5 mg, 150 mol) in ethanol (degassed '0.5 ml) Middle), and then 150 microliters of 2M Na2co3 (aqueous solution) (300 micromoles) was added. The reaction was allowed to proceed under Ar and Ar for 5 hours. The reaction was diluted with water (1 mL) and ether (1 mL). The organic phase was separated by vortexing, and 548271 A7 B7 was distilled. 5. Description of the invention (62) A crude product (compound 9, Ar = 3-trifluorotolyl) was obtained. 1 ml of TF A The crude product was processed and the Boc group was removed. After 30 minutes at room temperature, the TFA was evaporated to obtain the crude TFA salt. This salt was neutralized with 1M ΝΗΟΟΗ (1.0M) and extracted into ether (2 X 1 ml). Ether phase It was acidified with 4.0M HC1 (in Nisaki-yaki (200 μl)), and the HC1 salt was extracted into water (2 X 1 ml). The aqueous salt solution was washed with ether (2 X 1 ml), and the product was freeze-dried to obtain the product. (Compound 54, Ar = 3-trifluorotolyl) was a white powder (10 g, 39%). 1h NMR (CDC13) (Examination of 1.1 (br, 3H), 1.20 (br, 3H), 2.26 ( t, J = 5.6 Hz, 2H), 2.31 (t, J = 5.6 Hz, 2H), 2.88-2.91 (m, 4H), 3.27 (br, 2H), 3.52 (br, 2H). 7.10_7.47 ( m, * H). Analytical pair: Calculated C24H28N20F3Cl x 1.80 H20; c, 59.39; H, 6.56; N, 5.77; Found: C, 59.39; H, 5.90; N, 5.77. Example 2 8- 5 2 Following the same method as described for compound 5 4 in Example 27, but with the individual borane 3-trifluorotolylborane, the following compounds were also prepared. Example 2 8 Staff Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs Printed erbium, N -diethyl-4- (3 -Shi Xiao Phenyl · hexahydroxide _4 ^ subunits a, benzene Amine (Compound 55) using 3-nitrophenyl borane. This paper is suitable China National Standard Scale (CNS) A4 size (210 X 297 mm) 548271 A7 B7 V. invention is described in (63)

Η (55) 1Η NMR (CDC13) (base 1.11 (br, 3Η), 1.21 (br, 3Η), 2.27-2.34 (m, 4H), 2.92 (t, J = 6.0 Hz, 4H), 3.26 ( br, 2H), 3.52 (br, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.40-7.50 (m, 2H), 7.95-8.08 (m, 2H) Example 29 N, N-Diethyl-4- (4-tolyl-hexahydropyridine-4_ylidene-methyl) -phenylhydrazine (Compound 56) p-Tolylborane was used. 〇

1H NMR (CDC13) (Base 1.10 (br, 3H), 1.19 (br, 3H), 2.29 (s, 3H), -66-Printed by China National Standard (CNS) ) A4 specification (210X 297 mm) 548271 A7 B7 V. Description of the invention (64) 2.26-2.3l (m, 4H), 2.86-2.88 (m, 4H), 3.25 (br, 2H), 3.49 (br, 2H) ), 6.95-7.28 (m? 8H) Example 3 0 N, N -Diethyl-4-(4-methylammonium phenyl ^ -xylamine-copper-4 -subunit-methyl) -phenylhydrazone For the amine (compound 5 7) 4-methylformylphenylborane was used.

Printed by 1H NMR (CDC13) (Base 1.10 (br, 3H), 1.20 (br, 3H), 2.28 · 2 · 33 (ιη, 4Η), 2.89-2.92 (m, 4Η), 3.25 (br, 2Η), 3.50 (br, 2Η), 7.08-7 · 79 (π, 8H), 9.95 (s, 1H) Example 3 1 N, N -diethyl- 4- ( 3-Chloro-4-phenyl-pyridazol p-pyridine-4-ylidenemethyl) -benzidine (compound 58) is described using 3-chloro-4-phenyl phenylene. This paper is applicable to China Standard (CNS) A4 specification (210X 297 mm) 548271 A7 B7 V. Description of invention (65)

1H NMR (CDC13) (base 1.10 (br, 3H), 1.20 (br, 3H), 2.26-2.30 (m, 4H), 2.86-2.91 (m, 4H), 3.25 (br, 2H), 3.50 (br, 2H), 6.93-7.30 (m, 7H) Example 3 2 N, N -Diethyl-4-(4-Gaphenylphenylhexaamine p ratio -4-subunit · methyl)-benzylamine (compound 59) Use 4 · fluorophenylborane.

59 (59) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (1Η NMR (CDC13) (alkali) d l.ll (br, 3Η), 1.16 (br, 3Η), 2.25 (s, 4Η), 2.84 (s , 4H), 3.20 (br, 2H), 3.47 (br, 2H), 6.92 (m, 2H), 7.01 (m, 4H), 7.23 (d, J = 8.8 Hz, 2H) This paper standard applies to Chinese national standards (CNS) A4 specification (210X 297 mm) 548271 A7 B7 V. Description of the invention (66) Example 3 3 Ν, Ν-Diethyl-4- (2-fluorophenyl-hexahydroeodo-4- subunit -Methylbenzylamine (compound 60) uses a 2-gas phenyl shed. 〇

1H NMR (CDC13) (base 1.11 (br, 3H), 1.15 (br, 3H), 2.10 (t, J = 5.2 Hz, 2H), 2.27 (t, J = 5.2 Hz, 2H), 2.83 (m , 4H), 3.20 (br, 2H), 3.45 (br, 2H), 6.94-7.03 (m, 3H), 7.10-7 · 23 (ιη, 5H). Example 3 4 N, N-diethyl -4- (2,4-Difluorophenyl-hexahydropyridine-4-ylidene-methyl V benzamidine (Compound 61) uses 2,4-dichlorophenylborane. Ί (Please read the back first (Notes on this page, please fill out this page)

、 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 〇

This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 548271 ΑΊ B7 V. Description of the invention (67) 1H NMR (DMS0) (HC1 salt) d 1.07 (br, 6H), 2.24 (t, 2H ), 2.50 (t, 2H), 3.10 (t, 2H), 3.30 (t, 2H), 3.31 (br, 2H), 3.43 (br, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 9.20 (br, 2H) Example 3 5 N, N-Diethyl-4- (3,5-dichlorophenyl-hexahydropyridine_4-ylidenemethyl) -benzidine (Compound 62) Using 3,5-dichlorophenylboron alkyl.

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (62) 1Η NMR (DMS0) (HC1 salt) 6 1.03 (1) 1 *, 611), 2.36-2.38 (111,411), 3.0 · 3.2 (m, 4H ), 3.2 (br, 2H), 3.38 (br, 2H), 7.19 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.49 (s , 2H), 9.10 (br, 2H) Example 3 6 N, N -Diethyl-4- (3-ethylsulphonylphenyl · 7? Chloropeptide · 4 · subunit-methyl) -phenylhydrazone As the amine (compound 6 3), 3-ethylammonylphenylborane was used. This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 548271 A7 B7 V. Description of invention (68)

1H NMR (CDC13) (base 1.11 (br, 3H), 1.20 (br, 3H), 2.26 (t, J = 5.6 Ηζ, 2H), 2.32 (t, J = 5.6 Ηζ, 2H), 2.55 (s , 3H), 2.92-2.88 (m, 4H), 3.26 (br, 2H), 3.51 (br, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H) , 7.29 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.79 (d, J = 7.2 Hz, 1H) Example 3 7 N, N- Diethyl-4- (3,5-trifluorotolylhexahydropyridin-4-ylidene-methyl) -benzidine (Compound 64) 3,5-trifluorotolylborane is used. Central Ministry of Economic Affairs Printed by Standards Bureau Consumer Cooperatives 2 Β

CN Η 64) This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 548271 A7 B7 V. Description of the invention (69) 1H NMR (DMS0) (HC1 salt) d 1.06 (br, 3H), 1.08 (br, 3H), 2.33〇, 2Η), 2.41 (br, 2Η), 3.12 (br, 6Η), 3.38 (br, 2Η), 7.24 (d, J = 7.6 Ηζ, 2H), 7.30 (d , J = 7.6 Hz, 2H), 7.84 (s, 2H), 8.00 (s, 2H), 8.9 (br, 2H) Example 3 8 N, N_diethyl-4- (3 · phenylthio-hexa Hydropyridine · 4 · Subunit-methyl) -benzidine (Compound 65) 3-phenylthioborane was used.

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (65) 1Η NMR (DMS0) (HC1 salt 1.10 (br, 6Η), 2.44 (t, 2Η), 2.58 (t, 2Η), 3.10-3.15 (m, 4H ), 3.21 (br, 2H), 3.44 (br, 2H), 6.86 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H ), 7.33 (s, 1H), 7.52 (d, J 4.8 Hz, 1H) Example 3 9 — \ N, N-Diethyl-4- (2-phenylthio-hexahydropyridine · 4-subunit -Methyl) -benzamide (Compound 66) uses 2-phenylthioborane. The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 548271 A7 B7 V. Description of the invention (70)

1H NMR (CDC13) (base 1.12 (br, 3H), 1.20 (br, 3H), 2.24 (t, J = 5.2 Hz, 2H), 2.50 (t, J = 5.2 Hz, 2H), 2.85 (t, J = 5.6 Hz, 2H), 2.92 (t, J = 5.6 Hz, 2H), 3.27 (br, 2H), 3.51 (br, 2H), 6.75 (d, J = 3.6 Hz, 1H), 6.93 (t, J = 3.6 Hz, 1H), 7.16 (d, J = 7.2 Hz, 2H), 7.21 (d, J = 3.6 Hz, 1H), 7.30 (d, J = 7.2 Hz, 2H) Example 40 N, N-diethyl 4- (4-methylphenylsulfanyl-hexahydropyridine-4-ylidene-methyl) _benzidine (compound 67) uses 4-methylphenylthioborane. Employees of the Central Standards Bureau, Ministry of Economic Affairs Printed by Consumer Cooperatives 2 Et

e Μ s Ν Η \ n / (67 73 This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 548271 A7 B7 V. Description of the invention (71) 1H NMR (CDC13) (base) d l. ll (br, 3H), 1.20 (br, 3H), 2.32_2.75 (m, 4H), 2.45 (s, 3H), 2.90-2 · 87 (ιη, 4H), 3.26 (br, 2H) , 3.51 (br, 2H), 7.01 (d, J = 6.0 Hz, 2H), 7.10 (d, J = 6.0 Hz, 2H), 7.15 (d, J = 6.8 Hz, 2H), 7.27 (d, J = 6.8 Hz, 2H) Example 4 1 Ν, Ν · diethyl-4- (3-aminophenyl-hexahydropyridine-4 · ylidene-methyl) -benzidine (Compound 68) Using 3-aminebenzene Base house.

68, (68) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 1Η NMR (CDC13) (alkali) d l.ll (br, 3Η), 1.20 (br, 3Η), 2.27-2.33 (m, 4H), 2.86 -2.90 (m, 4H), 3.27 (br, 2H), 3.51 (br, 2H), 3.57 (br, 2H), 3.68 (s, 1H), 6.39 (s, 1H), 6.52 (dd, J = 1.6 Hz, J = 7.6 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 6.4 Hz, 2H), 7.26 (d, J = 6.4 Hz, 2H) Example 42-(N , N-Diethyl-4- (4-trifluorotolyl-hexahydropyridin-4-ylidene-methyl) -benzidine (Compound 69) 4-trifluorotolylborane is used. This paper Standards are applicable to China National Standard (CNS) A4 specifications (210X 297 mm) 548271 A7 B7 V. Description of invention (72)

Printed by 1H NMR (DMS0) (HC1 salt) dl.05 (br, 6H), 2.35 (t, 2H), 2.40 (t, 2H), 3.09 (m, 6H), 3.35 (br, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz , 2H), 8.71 (br, 2H) Example 43 N, N-diethyl-4- (4 · methoxyphenyl-hexahydropyridine-4-ylidene-methyl) · benzidine (Compound 7) ) Use 4-methoxyphenylborane.

This paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) 548271 A7 B7 V. Description of the invention (73) 1H NMR (CDC13) (base 1.12 (br, 3H), 1.19 (br, 3H), 2.29 (m, 4H), 2.87 (m, 4H), 3.27 (br, 2H), 3.51 (br, 2H), 3.77 (s, 3H), 6.80 (m, 2H), 7.00 (m, 2H), 7.10 ( d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz) Example 44, N, N -Diethyl- 4- (3,4-dichlorotyl-hexaazapine-pyridine-4-Asia -Methyl) _benzidine (Compound 71) 3,4-dichlorophenylborane was used.

Printed by 1H NMR (CDC13) (alkali) d 1.12 (br, 3H), 1.20 (br, 3H), 2.28 (t, J = 5.6 Hz, 4H), 2.89 (m, 4H) ), 3.27 (br, 2H), 3.52 (br, 2H), 6.8-7.4 (m, 7H) Example 45 N, N -diethyl-4- (2-digastolyl-hexaaza p-pyridine) Methyl) _benzidine (Compound 72) 2-trifluorotolylborane was used. This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 548271 A7 B7 V. Description of invention (74)

1H NMR (CDC13) (base) d 1.05 (br, 3H), 1.16 (br, 3H), 1.95 (π, 2H), 2.35-2.41 (m, 2H), 2.7-2.9 (m, 4H), 3.20 (br, 2H), 3.48 (br, 2H), 7.2-7.6 (m, 8H) Example 4,6 N, N-diethyl-4- (3-tolyl-hexapyridine-4- Subunit-methyl) -benzidine (Compound 73) m-Tolylborane was used. (Please read the precautions on the back before filling this page)

, 1T Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

1H NMR (CDC13) (base) d l.ll (br, 3H), 1.19 (br, 3H), 2.28 (s, 3H), 2.29 (m, 4H), 2.89 (m, 4H), 3.27 (br, 2H), 3.51 (br, 2H), 6.8-7.3 (m, 8H) This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 548271 A7 B7 V. Description of the invention (75) Example 47 N, N-Diethyl- 4- (2-methoxyphenyl-7T ammonia _4-subunit-methyl) -benzidine (Compound 7 4) 2-methoxyphenylborane was used. 〇

1H NMR (CDC13) (base) d 1.09 (br, 3H), 1.18 (br, 3H), 2.10 (q, J = 4.8 Hz, 2H), 2.31 (q, J = 4.8 Hz, 2H), 2.8-2.9 (m, 4H), 3.25 (br, 2H), 3.50 (br, 2H), 3.68 (s, 3H), 6.83-6.90 (m, 2H), 7.0 (d, 1H), 7.15 ^ 7.25 (m, 5H ) Example 48 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) N, N-Diethyl-4 · (3 · Methylphenyl-hexahydropyridine-4- Subunit-methyl) -benzimidamine (compound 7 5) 3-methylformylphenylborane was used. This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 548271 ΑΊ Β7 V. Description of invention (76)

Printed by 1H NMR (CDC13) (alkali) Θ 1.15 (br, 3H), 1.20 (br, 3H), 2.26-2 · 34 (ηι, 4Η), 2.90- 2.92〇, 4Η), 3.28 (br, 2Η), 3.2 (br, 2Η), 7.11-7.31 (m, 8Η), 9.96 (s, 1H) Example 49 N, N-diethyl-4 · ( 2-Amidino-hexahydropyridine-4-ylidene-methyl) -benzidine (Compound 76) 2-Amidinoborane was used.

2 B

This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 548271 A7 B7 V. Description of the invention (77) 1H NMR (CDC13) (alkali) d l.ll (br, 3H), 1.20 (br, 3H ), 2.35 · 2 · 39 (ιη, 4Η), 2.91-2.96 (m, 4Η), 3.27 (br, 2Η), 3.51 (br, 2Η), 7.16-7.40 (m, 5H), 7.42-7.44 (m, 2H), 7.57 (s, 1H), 7.72-7.79 (m, 2H). Example 5 0 N, N_Diethyl- 4- (2-methylpyridine phenyl-7T ammonium hydroxide_4_subunit_methyl) benzidine (compound 7 7) -Based borane. 〇

(77) 1H NMR (CDC13) (base 1.09 (br, 3H), 1.18 (br, 3H), 1.70-2.10 (m, 2H), 2.40-2.49 (m, 2H) ), 2.76-2.84 (m, 2H), 2.85-2.97 (m, 2H), 3.23 (br, 2H), 3.48 (br, 2H), 7.13-7.40 (m, 6H), 7.53-7.55 (m, 1H) ), 7.90 (d, J = 7.6 Hz, 1H), 10.27 (s, 1H) Example 5 1 N, N-diethyl-4- (4-ethylammonylphenyl · hexahydropyridine_4-subunit- Methyl) · Benzamidine (Compound 7 8) Use 4-Ethyl phenyl borane. The paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 548271 A7 B7 5. Description of the invention (78) n

Η, (78) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1Η NMR (CDC13) (base) d l.ll (br, 3Η), 1.20 (br, 3Η), 2.30-2.35 (m, 4H), 2.56 (s, 3H), 2.92 (m, 4H), 3.27 (br, 2H), 3.52 (br, 2H), 7.10_ 7.30 (m, 6H), 7.87 (d, J = 7.2 Hz, 2H) Example 5 2 N, N-Diethyl-4- (3-difluorotolyl-7T ammonia-4-ylidenemethyl) -benzidine (Compound 79) 3-trifluorotolylborane was used.

2 B

CF 9) This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 548271 A7 ___B7_ V. Description of the invention (79) 1H NMR (CDC13) (base) d l.ll (br, 3H), 1.20 (br, 3H), 2.26 (t, J = 5.6 Hz, 2H), 2.31 (t, J = 5.6 Hz, 2H), 2.88-2.91 (m, 4H), 3.27 (br, 2H), 3.52 (br, 2H), 7.10-7.47 (m, 8H) Example 5 3 N, N -monoethyl-4-[(l- (2,6_diamino group · hexyl hexachloro p ratio lake_4 -subunit Benzyl) -benzamine (Compound 80).

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. L-Boc-lysine (Cbz) (0.38 g, 1.0 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) at n2 at -15 ° C. Add N-methylmorphine (0.11 ml, 1.0 mmol), and then add isobutyl formate (0.13 ml, 1 mmol). After stirring for 10 minutes, add N, N-diethyl-4- (phenyl-hexahydropyridine-4-ylidene-methyl) -benzidine (compound 6, 0.35 g, 1.0 mmol in 1 ml) Tetrahydrofuran), the temperature was raised to 25 ° C for 2 hours. The reaction mixture was evaporated and placed on silica gel. MPLC (0 to 100% ethyl acetate in heptamine) on silica gel yielded 0.4 g. The product (0.40 g, 0.56 mmol) is dissolved in CH2C12 (10 ml) and the size of the paper is in accordance with the Chinese National Standard (CNS) A4 (210X297 mm) 548271 A7 ________B7 V. Invention Description (80) fluoroacetic acid (3 ml) was treated for 30 minutes and the volatiles were evaporated. The residue was dissolved in acetic acid (25 ml) and argon hydrolyzed on pd / C (10%, 0.10 g) at h2 (1 atm) for 1.5 hours. The solvent was evaporated and the residue was purified by chromatography on a short reverse phase (RP-18) column and dissolved with 0 to 30% acetonitrile (in water). The free amine was extracted with 5% K2CO3 / CH2Cl2 to obtain 123 mg, and then treated with 2 equivalents of HC1 (in methanol / H20). Freeze drying gives the dihydrochloride. 4 NMR (free state amine, CD3OD): d = 1.0-1.7 (m, 16H, fluoramine-Me, hexahydropyridine-H, lysine), 2.3-2.7 and 3.0-4.5 (m, 11H, fluoramine) -H, hexahydropyridine-H, lysine-H), 4.8 (s, 4H, 2NH2), 7.10-7.50 (m, 9H, Ar-H). C29H4〇N402 χ2 · 4 H20 x 2 Ηα, beard; C: 58.76; Η: 7.96; N: 9.43. Found 値: C: 58.70; Η: 7.51; Ν: 9.33. Example 5 4 4-"(4-Diethylaminemethylmethyl-phenyl) -phenyl-methylene 1-hexahydropyridine-1-carboxylic acid phosphono-oxymethyl ester compound 81 Printed by the Consumer Cooperatives of the Ministry of Standards

〇 〇I Η οηριο 〇 (81 This paper size applies the Chinese National Standard (CNS) A4 specification (210'〆297 mm) 548271 A7 B7 V. Description of the invention (si) N, N -diethyl- 4- ( Phenyl-7T hydride-4-ylidene-methyl) -benzamine (compound 6) (0.62 g, 1.8 mmol) was dissolved in CH2Cl2 (10 ml), and 1,8-bisbis was added Amine stubble (0.42 g, 2.0 mol). The solution was cooled to 0 ° C, and carbamic acid chloroformate @ Purpose (0.25 g, 2.0 mmol) in 1 ml of CH2C12 was added at 25 ° C. After 2 hours, first add another part of bisdiaminofluorene (0.21 g '1.0 mmol) and then add chloroformyl chloroformate (〇12 g, 1.0 mmol) for a total of 4 hours. After that, the solution was washed with 1 μH C1, brine, dried (MgS04) and evaporated to obtain 0.62 g. The residue was dissolved in toluene (25 ml), and difluorinated silver phosphate (0.81 g, 2.1 mol) was added. The mixture was heated at 8 (rc for 3 hours. The solution was filtered and washed with 5% K2C03 aqueous solution, brine, dryness (K2C03), and evaporated. MPLC (0 to 100% ethyl acetate (in heptane) on silica gel) ) To 0.66 grams (0.96 millimoles, 54%). The residue was dissolved in ethyl acetate (50 ml) and hydrogenolyzed (1 atm Η 2) with Pd / C (10%, 0.3 g) for 2 hours. After 遽 and evaporation of the solvent, the product was Two equivalents of na 〇Η (in methanol / water) were treated. The disodium salt of the product obtained by freeze-drying was a white solid. 1.20 (2m, 6H, pyramine-Me), 2.34 (m, 4H, hexahydropyridine-H) ), 3.19-3.61 (m, 8H, pyramine-CH2, hexahydropyridine_H), 5.44 (d, J = 13Hz, 2H, 0CH20), 7.18-7 · 36 (π, 9H, Ar-H ). Compounds 80 and 81 are suitable prodrugs of the compound of general formula (I), respectively. G) Synthesis of compound 55-57 Preparation of compounds 55, 56 and 57 compounds, as shown in Figure 7 below Method 84-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297mm). Please read the precautions below. I Binding Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, Printed by Consumer Consumption Cooperative 548271 A7 B7 Five 'Invention Description (82

• Grasshopper Chlorine / TEA 2. R = Ma P Lin Hexammonia ^ 7 Than Dian Ye Dagger slightly Figure 7

R = morpholine (82) g Liurubi bite (83)

1. 3_F-Ph-B (〇H2) Pd (0) / Na2CO3 2. HCI (Please read the precautions on the back before filling this page} &amp; clothing ·

P

R = 1 morpholine (85); Example 55 R =! Hexahydropyridine (86); Example 56 R = Pyrrolidine (87); Examples 57 and 11 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (i) 4- {Bromo [4- (morpholinecarbonyl) fluorenyl} methylene 丨 hexahydropyridine # acid tributyl ester (compound 82) was prepared by compound 51 (0.25 g, 0.625 mmol) prepared according to Figure 6 ) And a solution of freshly distilled triethylamine (0.5 ml) in CH2C12 (12 ml) at 1 *: 1 :. dropwise addition of oxalic acid chloride (0.38 liters, 2.0) ^ 1, 0.7 &lt; 5 millimoles). The solution was stirred at r.t. for 10 minutes, and the solvent and excess reagents were removed by evacuating to obtain the crude product, which was used in the next step without further purification. Add morpholine (56ml, 0.65mmol) to Chlorine (0.65mmol) and three -85. This paper size is applicable to China National Standards (CNS) A4 size (2 丨 0 × 297 male directors) 548271 A7 B7

A solution of ethylamine (0.5 ml) in CH2C12 (5 ml). The reaction was allowed to proceed at r.t. for 1 hour. The solvent was removed by emptying. The crude product was partitioned between ethyl acetate (25 mL) and water (25 mL). The aqueous layer was washed with ethyl acetate. The combined ethyl acetate was 2M NaOH (2x25 mL), 2M HC1 (2X25 mL), and brine. (1 X 25 mL), and dried on MgSCU. The product was removed by emptying the solvent (Compound 82) (294 mg, 97% yield). 4 nmr CDC13 (400 MHz) 1.44 (s, 9H), 2.21 (t, J = 5.6 Hz, 2H), 2.62 (t, J = 5.6 Hz, 2H), 3.31 (t, J = 5.6 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.69 (br, 8H), 7.31 (d, J = 6.4 Hz, 2H), 7.37 (d, J = 6.4 Hz, 2H). (ii) Preparation of 4- {bromo [4- (hexahydropyridinecarbonyl) phenyl 1 methylene di-hexahydropyridinecarboxylic acid tert-butyl ester (Compound 8 3) was prepared as described for the preparation of Compound 82 Method, but using hexaargyridine molybdenum 04 nmr CDC13 (400 MHz) 1.44 (s, 9H), 1.51 (br, 2H), 1.66 (br, 4H), 2.21 (t, J 2 5. 6 Hz , 2H), 2.62 (t, J = 5.6 Hz, 2H), 3.31 (t, J = 5.6 Hz, 2H), 3.33 (br, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.68 (br, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H). Printing of bromine by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 丨 4- (tetrahydro-1H_1-pyrrolecarbonyl) phenyl 1 methylene oxide 1-hexahydropyridinecarboxylic acid third butyl ester (Compound 84) The method described in the preparation of 82, but using pilodol instead of morphine. 4 nmr CDC13 (400 MHz) 1.44 (s, 9H), 1.87 (} J = 6.8 Hz, 2H), 1.95 (q, J = 6.8 Hz, 2H), 2.20 (t, J = 5.6 Hz, 2H), 2.62 (t, J = 5.6 Hz, 2H), 3.31 (t, J = 5.6 Hz, 2H), 3.43 (t, J = 6.8 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.63 (t , J = 6.8 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H) This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) B7 V. Description of the invention (84) Example 5 5 1: [(3 — 1 ^ _. 棊) _. Baoshimpyridin-4-yl-methyl 1-sonon-morpholine 4-yl · Tone (compound 8 5) | In compound 82 (37 g, 0.082 mmol) and (triphenylphosphine) palladium (0) (5 mg, 0.0043 mmol) in xylene (degassed, 〇5mL) solution, add 3-fluorophenylboron (25mg, 0.18mmol) (in degassed ethanol '0.5 升 liter), and then add 150 microliters 2M Na2C03 (aqueous solution) (300 Micro moles). The reaction was allowed to proceed at 80 ° CAr for 2 hours. The reaction was diluted with water (0 liters) and ether (1¾ liters) and vortexed. The organic phase was separated and evaporated to give the crude product, which was used without further purification. The crude product was treated with 1 ml of THF to remove the Boc group. After 30 minutes at r t, the TFA was evaporated to obtain the crude TFA salt. This salt was neutralized with 1M NH4OH (1.0M) and pumped into ether (2 x 1¾ liters). The ether phase was acidified with 4.0M HC1 (in 200 microliters of dioxane) and the HC1 salt was pumped into water (2 X 1 mL). The aqueous salt solution was washed with ether (2 x 1 ml) and freeze-dried to give the product as a white powder. 1h NMR CDC13 (400 MHz) d2.67 (m, 4H), 3.19 (m, 4H), 3.45 (br, 2H), 3.68 (br, 6H), 6.75 (d, J = 9.6 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.95 (m, 1H), 7.11 (d, J = 7.6 Hz, 2H), 7.25 (s, 1H), 7.35 (d, J = 7.6 Hz, 2H) 5 6 4-[(3-Fluoroyl-based p-pyridine-4-yl-fluorenyl 1-phenyl-hexaamino p-pyridine_i_yl-methanone (Compound 86) is prepared as for compound 8-5 The method described in the preparation, but using the compound 8 3 as the starting material. -87-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 548271 A7 B7 V. Description of the invention (85) 4 NMR CDC13 ( 400 ΜΗζ) θ 1.51 (br, 2H), 1.65 (br, 4H), 2.60 (br, 4H), 3.14 (br, 4H), 3.33 (br, 2H), 3.68 (br, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.25 (s, 1H) , 7.32 (d, J = 8.4 Hz, 2H). Example 5 7 4-[(3-Merphenyl) _Hexachlorocyclopyridine-4-yl-methyl] -phenyl pbilodine-1- The methyl ketone (compound 87) is prepared as described for compound 85, but using compound 84 as the starting material. [H NMR CDCI3 (400 MHz) ά 1.84-1.89 (m? 2H)? 1.90-1.98 (m9 2H), 2.60-2.63 (m, 4H), 3.13-3.17 (m, 4H), 3.41 (t, J = 6.8 Hz, 2H ), 3.62 (t, J = 6.8 Hz), 6.73 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 6.93 (m, 1H), 7.10 (d, J = 8.0 Hz, 2H), 7.25 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H). H) Preparation Example 5 Synthesis Diagram of 8-68 Compound Example 5 Preparation of 8-68 Compound, according to the following diagram 8 (a)-(c). (Please read the notes on the back before filling out this page) The paper size printed by the Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 548271 A7 B7 V. Description of the invention (86 ) Figure 8 (a) 〇

R = OEt (88) R = Et2N (89) R = OMe (90) R = i-PrO (91) Sasaki (Please read the notes on the back before filling this page) Ύ

ry

H

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs HR = 〇Et (96); Ex. 58 R = Et2N (97) R = OMe (98) R = i-PrO (99) R = 〇Et (92) R = Et2N (93) R = OMe (94) R = i-PrO (95) 89 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 548271 A7 B7 V. Description of invention (87) Figure 8 ( b)

F

Η

T R

9 66: 5X..6 EX.EEX 1000 (10rNwo Etkw ^ r 〇E〇ip R = R = R = R = (Please read the notes on the back before filling this page) R = 〇Et (104); Εχ · 66 R = Et2N (105) R = ΟΜθ (106); Ex. 65 R = i-PrO (107); Ex. 63 This paper size applies to the Chinese National Standard (CNS) A4 specifications (210X297 mm) 548271 A7 B7 V. Description of the invention (88 Figure 8 (c) CH. ⑴

巳 nBr / TEA Ϊ CH.

Η R = OEt (IOO) Ex. 59 R = Et2N (101) R = OMe (102) R ^ i-PrO (103)

R = OEt (108); Ex. 61 R = Et2N (109) R = OMe (110) R = Bu Pr〇 (111) (Please read the precautions on the back before filling this page) (ϋ) Ϊ

BnBr / TEA I H

V

R = 〇Et (104); Ex. 66 R = Et2N (105) R = OMe (106); Ex65 R = i-PrO (107)

R = OEt (112)) R = Et2N (113) R = OMe (114) R = i-Pr〇 (115) (iii) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Ϊ

H

BnBr factory TEA I H R = OEt (96) R = Et2N (97) R = OMe (98) R = i-PrO (99); Ex. 67 -91 rt

H

This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 8 54 A7 Five printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs _____B7__ Description of the invention (89) (i) 4- [Bromo- (4 -Acetylamine-phenyl) -methyl hexahydropyridine-1-carboxylic acid tributyl ester (Compound 8 8) was prepared from Compound 51 according to Figure 6, (0.25 g, 0.625 mmol) Ear) in toluene (5 ml), add diphenylphosphonium azide (0.192 g, 0.70 mmol) and triethylamine (0.1 ml, 0.7 mmol) under Ar, 95X: stir the mixture After 2 hours, excess ethanol (2 ml) and triethylamine (0.1 ml) were added, and the solution was stirred at 95 ° C for another 15 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ether. The ether layer was washed with water, dried over MgS04, and removed by emptying to obtain the product (Compound 88) and a yellow-brown foam (300 mg, 99% yield). lR NMR (400 MHz) (CDCl3) 1.30 (t9 J = 7.2 Hz? 3H), 1.44 (s, 9H)? 2.22 (t, J = 6.0Hz, 2H), 2.60 (t, J = 6.0 Hz, 2H) , 3.31 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 6.0 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 6.58 (s, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H) 〇 (4-ethoxycarbonylaminophenyl)-(3-fluoromossylmethyl 1-hexaxinpipine 1-carboxylic acid third butyl Preparation of the ester (Compound 92) Coupling of 4 kinds of vinyl bromide (Compound 88-9 1) with 3-fluorophenylborane in sozaki was performed in parallel. The reaction and liquid-liquid extraction were performed in a 25 mm X 150 mm culture tube It is carried out in the form of a typical plan. The compound 88 (0.30 g, 0.625 mmol) and the compound (triphenylphosphine), Pd (O) (50 mg) in toluene (degassed) , 5 ml), add% fluorophenylboron pits (0.182 g, 1.3 mmol) in ethanol (degassed, 5 ml) and then add 0.75 ml 2M Na2C03 (aqueous solution). 5 millimoles). The reaction was allowed to proceed at 80 ° C for 3 hours under Ar. The reactants were diluted with water and ether and vortexed. This paper is sized to the Chinese National Standard (CNS) A4 specification (210X297 public director) 548271 A7 B7 5. Description of the invention (90). The organic phase was separated and evaporated to give the crude product. The crude product was purified by silica gel chromatography (0-50% EtOAc in hexane) to give the crude product (Compound 92) as a white powder (0.166 g, 58% yield). NMR (400 MHz) (CDCl3) d 1.25 (t, J = 7.2 Hz 3H), i 44 (s, 9H), 2.27-2.33 (m, 4H), 3.41-3.44 (m, 4H), 4.20 (q , Wind 2 Hz, 2H), 6.52 (s, 1H), 6.76 (d, J: 10 Hz, 2H), 6.85-6.89 (m, 2H), 7.01 (d, J = 8.8 Hz, 2H), 7.19- 7.23 (m, 1H), 7.28 (d, J = 8.8 Hz, 2H) 'Example 5 8 t [(3 · fluorophenyl) -hexahydro late _4_yl-methylphenylbenzene-aminomethyl The ester (Compound 96) was prepared in a test tube (13 mm x 100 mm), and the removal of the B 0 C protecting group was performed in parallel on a small scale. A typical method is described below. Compound 92 (50 μg, 0.11 mmol) was treated with HC1 (in dioxane (4.0 M, 2 mL)) to remove the BOC group. The mixture was stirred at room temperature for 30 minutes.眞 2 After removing the solvent and H C1, freeze-drying gave the product compound 96 as white powder (40 mg, 99% yield). 4 NMR (400 MHz) (CDCl3) (y 1.28 (t, J = 7.2 Ηζ, 3Η), 2.27-2.3l (m, 4H), 2.85-2.91 (m, 4H) ), 4.19 (q, J = 7.2 Hz, 2H), 6.50 (s, 1H), 6.76 (d, J = 10Hz, 1H), 6.85-6.89 (m, 2H), 7.0 (i, d, J = 8.8 Hz, 2H), 7.19-7.23 (m, 1H), 7.28 (d, J = 8.8 Hz, 2H). Example 5 9 4-[(3-Fluorophenyl) -hexahydropyridin-4-yl-methyl The production of gibbenzyl methyl urethane (compound 100) was carried out in a test tube (13 mm x 100 mm) in a small scale in parallel. 93-This paper applies Chinese national standards (CNS) A4 specification (210x29T ^ jy 548271 A7 B7 V. Description of the invention (91) The alkylation of amine nitrogen, the typical method is summarized below. In compound 92 (50 mg, 0.05 umol) in CH2Cl2 ( 15 ml), add methyl iodide (31 mg, 0.22 mmol), NaOH aqueous solution (1.0¾L, 2M) and tetrabutylammonium sulfate (44 mg, 0.13 mmol) Ear). The solution was refluxed for 1 hour. After cooling to room temperature, CH2C12 was separated and evaporated. Add ether to the residue and filter to remove tetrabutyl iodide. Ammonium. The ether was removed by emptying to obtain the crude product Compound 100 as a clear oil. The above was treated with HC1 in Erzaki to remove the boC group, and the product was white powder (17 mg, 42% yield) after freeze-drying. NMR (400 MHz) (CDCl3) cn.23 (t, J = 7.2 Hz, 3H), 2.27-2.33 (m, 4H), 2.85-2.91 (m, 4H), 3.26 (s, 3H), 4.15 (q, J = 7.2 Hz, 2H), 6.78 (d, J = 10 Hz, 1H), 6.85-6.89 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H) 7.19-7.23 (m, 1H). Example 6 0 4-[(l-fluorenylhexahydropyridin-4-yl)-(3-phenyl) -methyl] -phenyl-carbamic acid ethyl The ester (Compound 1 16) was prepared in a test tube (13 mm x 100 mm) and the benzylation of Compound 100 was performed on a small scale in parallel. A typical method is outlined below. Central Standards Bureau, Ministry of Economic Affairs Printed by the employee consumer cooperative (please read the precautions on the back before filling this page). Add ΝΗ4ΟΗ (1M, 0.5 ml) to the aqueous solution of compound 100 (0.046 mmol) to obtain the free base form of compound 100, and Extracted in ether. The ether was removed by emptying to obtain an oil, which was dissolved in CH2C12 and treated with benzyl bromide (0.14 ml, 0.5M in CH2C12 *) and triethylamine (0.05 ml). The solution was stirred at room temperature for 5 hours. The solvent was removed by emptying. The product was dissolved in water / acetonitrile / HC1 (2: 1: 0.5M) and freeze-dried to obtain product compound 108 as a white powder. _-94-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) &quot; &quot; '548271 A7 _B7___ V. Description of the invention (92) Please read the notes of the back first! H NMR (400 MHz ) (CDC13) ^ 1.28 (t? J = 7.2 Hz 3H)? 2.33-2.36 (m? 4H), 2.38-2.46 (m, 4H), 3.51 (s, 2H), 4.19 (q, J = 7.2 Hz, 2H), 6.50 (s, 1H), 6.78 (d, J = 10 Hz, 1H), 6.85-6.89 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H) 7.19 · 7 · 30 ( ιη, 7H). Example 6 1 6 8 The following compounds were also prepared according to the synthetic routes described in Schemes 8 (a)-(c). Table 1 Characterization data of the chemical structures of the example compounds I1 H NMR; 400 MHz (CDCl3)] Figure 61 108 δ 1.17 (t, J = 7.6Hz, 3H), 2.28-2.35 (m, 4H), 2.40-2.45 (m , 4H), 3.21 (s, 3H), 3.50 (s, 2H), 4.10 (q, J = 7.2 Hz, 2H), 6.73 (d, J = 8.7 Hz, 1H), 6.85 (m, 2H), 7.01 (d, J = 8.8 Hz, 2H), 7.2-7.3 (m, 8H) 8 (c) 62 103 Η δ 1.21 (d, J = 6.8Hz, 6H), 2.28 (t, J = 5.6 Hz, 2H) , 2.31 (t, J = 5.6 Hz, 2H), 2.88 (t, J = 5.6 Hz, 4H), 3.25 (s,? H), 4.93 (quin, J = 6.0 Hz, 1H), 6.78 (d, 1H ), 6.87 (d, 2H), 7.04 (d, 2H), 7.14 (d, 2H), 7.15-7.29 (m, 2H) 8 (b) Printed by the Central Government Prospective Workers Cooperative -95-This paper Standards are applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) 548271 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (93) Table 1 (continued) Characterization data of chemical compounds of example compounds i1 H NMR 400 MHz (CDCl3)] (3 shows 63 107 Η δ 1.14 (t, J = 7.2 Hz, 3H), 1.20 (d, J = 6.4 Hz, 6H), 2.92 (t, J = 5.2 Hz, 2H), 2.33 (t, J = 5.2 Hz, 2H), 2.90 (t, J = 5.2 Hz, 4H), 3.66 (q, J = 7.6 Hz, 2H), 4.9 3 (quin, J = 6.0 Hz, 1H), 6.79 (d, 1H), 6.88 (d, 2H), 7.02 (d, 2H), 7.15 (d, 2H), 7.18-7.25 (m, 2H) 8 ( b) 64 102 Η S 2.27-2.33 (m, 4H), 2.88-2.90 (m, 4H), 3.27 (s, 3H), 3.70 (s, 3H), 6.79 (d, 10 Hz, 1H), 6.88- 6.90 (m, 2H), 7.06 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.20-7.25 (m, 1H) 8 (b) 65 106 Η δ 1.13 (t , J = 6.8Hz, 3H), 2.27-2.33 (m? 4H), 2.88-2.90 (m, 4H), 3.67 (s, 3H), 3.68 (q, J = 6.8Hz, 2H), 6.79 (d, 10 Hz, 1H), 6.88-6.90 (m, 2H), 7.06 (d, J = 8.4 Hz, 2Η), 7.13 (d, J = 8.4Hz, 2H), 7.20-7.25 (m, 1H ) 8 (b) (Please read the notes on the back before filling out this page) This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 548271 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention (94) Table 1 (continued) Example | Characterization data of chemical structure of compound [] H NMR; 400 MHz (CDCl3)] Figure 66 104 Η δ 1.13 (t, J = 6.8Hz, 3H), 1.21 ( t, J = 7.2 Hz, 3H), 2.30-2.36 (m, 4H), 2.91-2.93 (m, 4H), 3.67 (q, J = 6.8 Hz, 2H), 4.13 (q, J = 6.8 Hz, 2H ), 6.79 (d, 10 Hz, 1H), 6.88-6.90 (m, 2H), 7.06 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.20-7.25 (m, 1H) 8 (b ) 67 99 Η δ 1.26 (d, J = 6.0 Hz, 6H), 2.27-2.32 (m, 4H), 2.87-2.89 (m, 4H), 4.95-5.02 (m, 1H), 6.56 (s, 1H ), 6.79 (d, 10 Hz, 1H), 6.88-6.90 (m, 2H), 7.01 (d, J = 8.4 Hz, 2H), 7.20-7.25 (m, 1H), 7.27 (d, J = 8.4 Hz , '2H) 8 (b) (Please read the notes on the back before filling in this page) This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 548271

\ Description of the invention (95) tl (continued) Example, chemical structure of the compound, characterization data diagram I1 H NMR; 400 MHz (CDCl3)] 68 98 5 2.27-2.31 (m, 4H), 2.86-2.89 (m, 4H ), 3.75 (s, 3H), 6.64 (s, 1H), 6.76-6.80 (m, 8 (b) 1H), 6.85-7.00 (m, 2H), Η 7.02 (d, J = 8.8 Hz, 2H) , 7.18-7.22 (m, 1H), 7.28 (d, J = 8.8 Hz, 2H) Please read the note on the back before filling out this page Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Printed currently known to carry out the invention The best way is to use compounds 6,7,9,10,12,26,27,34,39,44,58,59,62,69,71,104,106 and 109. Lip composition according to the present invention The novel compounds can be administered orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, extradurally, intrathecally, intraventricularly, and by injection into the joints. The preferred route of administration is oral, intravenous or intramuscular &lt;. The dosage will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors that are usually considered by the attending physician when deciding on the most appropriate therapy and dosage for each particular patient. -98 This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 548271 A7 B7 V. Description of the invention (96 For the preparation of pharmaceutical compositions from the compounds of the present invention, inert, medically acceptable carrier It can be solid or liquid. Preparations in solid form include powders, bonds, dispersing granules, capsules, cachets, and suppositories. A solid carrier can be more than one substance, and it can also act as a diluent, bridging agent , Solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be encapsulated. In powders, the carrier is a finely divided solid that is mixed with the finely divided active components. In tablets In the process, the active ingredient is mixed with a carrier having the necessary cohesive properties in a suitable ratio, and then compacted into the required shape and size. For the preparation of suppository compositions, a low melting wax such as fatty acid glyceride and cocoa butter is firstly used. The mixture is melted, and then the active ingredients are dispersed by, for example, stirring. The molten homogeneous mixture is then poured into a conventional size mold and allowed to cool and solidify. A suitable carrier is MgS03, stearic acid , Talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting point, cocoa butter, etc. The pharmaceutically acceptable salts are acetate, Benzenesulfonate, benzoate, bicarbonate, tartrate, bromide, calcium acetate, carsylate, carbonate, chloride, citrate, dihydrochloride, ethylenediaminetetraacetate, edisylate, acid Hydrocarbyl, diacetate, fumarate, glucaptate, gluconate, glutamate, ethanol-p-aminophenylarsonate, hexyl isophthalate, hydrabamine, hydrobromide, Hydrochloride, hydroxyammonium salt, iodide, 2-isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide ____- 99-This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X-1297) (Please read the precautions on the back before filling out this page), 1 'Printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 548271 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (97 ) Acid salt, methyl nitrate, methyl sulfate, mucate salt, napsylate, sodium salt, embonate, cold acid salt, acid salt / ditrans acid salt, polygalacturonic acid Salt, salicylate, stearate, basic acetate, succinate, sulfate, tannin, tartrate, teoclate, triethiodide, benzathine, chloroprocaine Salt, choline salt, diethanolamine salt, ethylenediamine salt, megluniine salt, procaine salt, Ming, grape, iridium, iron, bell, sodium and zinc salts. Preferred medically acceptable Accepted salts are hydrochloride and citrate. The term composition means a formulation comprising capsules comprising an active ingredient and an encapsulating substance as a carrier, in which the active ingredient (with or without other carriers) is enclosed by the carrier. The carrier and the active ingredient Associate. Similarly, cachets are included. Lozenges, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Liquid forms include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds can be provided for parenteral administration Examples of liquid preparations. The liquid composition can also be formulated into a solution in an aqueous polyethylene glycol solution. Aqueous solutions for oral use can be prepared by dissolving the active ingredients in water and adding suitable colorants, flavoring agents, stabilizers and thickeners if necessary. Aqueous suspensions for oral use can disperse the active ingredients of the components in water and viscous substances such as natural synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other suspending agents known in the pharmaceutical formulation technology While prepared. i Preferably, the pharmaceutical composition is in the form of a unit dose, in which the composition is divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged preparation, which contains discrete quantities of preparation, such as the hinge of the packaging _______-100-This paper size is suitable for wealth® &quot; 5 * ^ 5 ^ CNS) A4 size (210X297 mm) '' —-- (Please read the notes on the back before filling this page)

548271 V. Description of the invention (98 The staff of the Central Standards Bureau of the Ministry of Economic Affairs consumes printed preparations, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule, a sachet or a lozenge itself, or it can be appropriate Any of these packaging forms. Biological estimates A) In vitro model 1 Cell culture. Human 293 S cells expressing colonized human A, d, and% receptor and neomycin resistance were grown at 37. Suspension in a shake flask containing calcium-free DMEM 10 / 〇FBS '5 / 〇BCS' 0.1% piuronic f-68 and 600 μg / ml geneticin at ° C and 5% C02. Membrane preparation cells were pelleted into Shendian and resuspended in lysis buffer (50 mM Ttis, pH 7.0, 2.5 mM EDTA). PMSF was added from a 0.1 M stock solution in ethanol before use. To lmM), incubate on ice for 15 minutes, and homogenize with polytron for 30 seconds. Place the suspension in 4. 〇 Rotate 10 minutes at 1000 g (maximum). The supernatant was kept on ice and the pellet was resuspended and spun as before. The supernatants from the two spins were combined, and the pellet was re-suspended at 46,000 g (maximum) at 30 ° and resuspended in cold Tris buffer (50 mM Tris / ci, P · 〇). Spin. The obtained pellet is resuspended in membrane buffer (50 mM Tris, 0.32M sucrose, pH 7.0), frozen in dry ice / ethanol with 4 knives (1¾ liters) in a polypropylene tube, and stored in _7 〇π until use. Protein concentration was determined by modified LOwry assay and 81) 8. Combined with the measurement, thaw the membrane at 37 C, cool it on ice, and dilute it by 25 metering needles 3 times (please read the precautions on the back before filling this page) Ding ---____-101 A paper scale made in China ^ 7 ^ 7 ^ grid (2ι〇χ ^^^ y 54827ι A7 B7 i, description of the invention (99) in binding buffer (50 mM Tris, 3 mM MgCl2, 1 mg / ml BSA (Sigma A_7888); Η 7 · 4 After passing through a 0.22 m filter membrane, it was stored at 4 ° C after filtration, and 5 μg / ml aprotinin, 10 &quot; M bestatin, 10 diprotin A, without DTT) was added thereto. 100 microliters (for protein For micrograms, refer to Table 1) to a frozen 12X75 mm polypropylene tube containing 100 microliters of the appropriate radioligand (see Table 1) and 100 microliters of the test peptide at various concentrations. The total (TB) and non-specific (NS) binding were measured in the presence of 10 "M nanosson. The tube was vortexed and incubated at 25 C for 60-75 minutes, after which the contents were quickly emptied and filtered, and Approximately 2 ml / tube of frozen washing buffer (50 mM Tris, pH 7.0, 3 mM MgCh) was pre-soaked in 0.1% polyextension Wash the GF / B filter (Whatman) with imine for at least 2 hours. After soaking the filter in a mini vial containing 6-7 ml of scintillation liquid for at least 12 hours, measure the radioactivity (dpm) retained on the filter with a theta counter. If the measurement system is established in 96 deep well plates, the filtration is on a single-filtration membrane immersed in 96 PEIs. They are washed with 3 X 1 liter washing buffer and dried in an oven at 55 ° C. 2 hours. The filter plate was counted in T〇pc〇unt (Packard) after adding 50 microliters of MS-20 flash solution / hole. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Analysis (please read the back Note: Please fill in this page again) Calculate the specific binding (SB) as TB-NS, and the SB in the presence of various test peptides is expressed as the percentage of the control group SB. For the specific replacement of the binding in the radioligand ligand The 1C50 値 and Hi 11 coefficients (nH) of the bit body are calculated from logit plots or curve preparation programs such as Ligand, GraphPad Prism, SigmaPlot, or ReceptorFit. K !! is calculated from the Cheng-Prussoff equation. IC50, Ki and ηΗ average paper size applicable National Standards (CNS) Α4 specifications (210Χ29? Mm) 548271 Α7 Β7 V. invention is described in (100) Zhi soil S · E · Μ. Zhi's report is coordinating body for at least three displacement curves of the test. Receptor saturation experiment The determination of the radioligand KcT 値 is based on the concentration range from 0.2 to 5 times of κβ (if the required amount of radioligand is feasible, up to 1 () times) Appropriate radioligands for binding assays on cell membranes. Specific radioligand binding is expressed as picomoles per milligram of membrane protein. The K β and B m a X of the individual experiments were obtained from the non-linear coordination of the individual specific binding (B) to the nM free state (F) radioligand according to a Shore pattern. B) Biological mode (in-vivo mode) Freund's complete adjuvant (FCA), and MECHANO-ALLODΥΝΙΑ induced by mechanical stimulation of rat's sciatic annulus (please read the back first) Note: Please fill in this page again.) R Pack _ Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Use male Sprague-Dawley rats (Charles River, St. Constant, Canada) to weigh 175-200 grams. They were kept in groups of 3 at a temperature of 20 ° C, with a 12:12 hour light / dark cycle, and free access to food and water. Arrive at and allow the animals to acclimate to the environment for at least 2 days before surgery. This experiment was approved by the appropriate Medical Ethics Committee for animal research. Experimental method Diroind's complete adjuvant The rats were first anesthetized in a halothane chamber, and thereafter, 10 microliters of FCA was injected subcutaneously into the dorsal area of the left foot between the second and third external toes. Then let the animals (milk milk) 8 size (210, 乂 297 mm) 548271 A7 B7 V. Description of the invention (101) Observed in the cage where they live, recover from anesthesia. The sciatic nerve ring needs to be prepared according to the method described by Mosconi and Kruger (1 996). Rats are anesthetized intraperitoneally with a mixture of ketamine / toluene P-sepocin (2 ml / kg) and placed on the right side, and then along the left femur Slice the outside axis. Pull out the muscles of the upper quadriceps to reveal the sciatic nerve, and wrap the plastic ring band (PE-60 tube, 2 mm long) on it. The wound was closed with 3-0 silk sutures in 2 layers. The VON FREY test was used to determine the mechanical stimulation of the heterodynamic forces (MECHANO-allodynia ^ between 08:00 and 16:00, using the method described by Chap lan et al. (1994). Rats were placed in Plexiglas on the top of the barbed wire bottom. In the cage, it is close to the soles of the feet, and it makes the habits 10-15 points. The test area is the sole of the left midfoot, avoiding less sensitive foot pads. Increase the stiffness of the soles with a set of 8 pairs of logs Degrees (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51 and 15.14 grams; Stoelting III, USA). Von Frey hairs are applied from under the net perpendicular to the soles of the feet with sufficient force to make the opposite feet The palm causes a slight twist and is maintained for about 6-8 seconds. If the palm of the foot quickly withdraws the positive response. It is also considered a positive response if the hair is immediately retracted after removal of the hair. Movement is considered an ambiguous response, here The test plan was repeated on the first day after surgery for the FCA treated group and on the seventh day after surgery for the sciatic annulus group. Animals were tested using the Dix X ο upper-lower method (1 9 80) determine the 50% withdrawal threshold. The test starts with 2.04 grams of hair, It is the middle of the whole group ___-104-This paper size is applicable to Chinese National Standard (CNS) Α4 specification (210X297 mm) Please read the precautions beforehand, i% Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 548271 A7 ___ B7 V. Description of Invention (102). The stimulus is always provided in a continuous manner, regardless of whether it is rising or falling. In response to the initial withdrawal of the wool, the Stronger stimulus; in the case of withdrawing of the feet, 'select the next weaker stimulus. The calculation of the optimal threshold for this method requires 6 responses in the immediate vicinity of the 50% threshold, and when the first change in response occurs When, for example, the threshold is crossed for the first time, these 6 reactions are counted. When the threshold falls outside the range of the stimulus, it is designated as 15.14 (normal sensitivity) or 0.41 (maximum different power (&amp; 11〇 ( 1 丫 111 (:)). Use the conventional method to list the types of 1% sexual and negative reactions obtained, X = no withdrawal; 0 = withdrawal, and use the following formula to interpolate 50% withdrawal threshold: 50 % (Gram) threshold = 10 (Xf + h) / l0,000 where Xf = all Use the last von Frey's 値 (logarithmic unit); k = Table 値 (from Chaplan et al. (1994), for the type of positive / negative reactions; and &amp; = mean difference between stimuli (log unit). Here, Θ = 224. According to Chaplan et al., 194, the von Frey threshold is converted to the percentage of maximum possible effect (% MPE). The following formula is used to calculate the% 卩 MP% MPE = threshold (g) of drug treatment-allodynia threshold (g) X 100 threshold (g) of control group-allodynia threshold (G) Test substance administration Before the von Frey test, rats were injected with the test substance (subcutaneously, intraperitoneally, or orally). The time between the administration of the test compound and the v 0 n Frey test was determined by the test compound. Depending on the nature. Definition: The following abbreviations are indicative: -105-This paper size applies Chinese National Standard (CNS) A4 (21〇χ 297 mm;) (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 548271 A7 B7 V. Description of the invention (103) A c = B S &amp; Ar = aryl t-BOC = third butoxycarbonyl t-Bu = third butadiene base

Et = ethyl iPr = isopropyl

Me = methyl

Ph = phenyl

Pr = propylrt = room temperature TFA = trifluoroacetic acid THF = tetrahydrofuran TMEDA = N, N, N ', N'_tetramethylethylenediamine This paper size is applicable to Chinese National Standard (CNS) A4 specifications ( 210X297mm) -------- · .Install ------ Order ---------- ^ ~ &quot; 7 (Please read the precautions on the back before filling this page) 1 Announcement-Application date 86. 12 · 08 Case No. 086118465 Category

A

7 9 J. IT Black _ "Patent Specification _ Invention, · Type name Chinese with a novel analgesic double-bond hexahydro P ratio lake derivative English &quot; NOVEL PIPERIDINE DERIVATIVES HAVING AN EXOCYCLIC DOUBLE BOND WITH ANALGESIC EFFECTS 11 Name nationality

Invention, Creation A Residence, Residence 1. Daniel Dellammy 2. Edward Roberts 3. Hong Yang Wei 1.3. Both Canada 2. United Kingdom 1. British Columbia · Canada 793 Chabonho Road 793 St. Lhasa Quebec Canada 2. Saint Quebec Canada No. 2541, Chatena Center, Lhasa Wardell, 3775 1 Anthony-Fagan Road, Pierfield, Quebec, Canada

Name (Name) Canadian Commercial Astor Pharmaceutical Company Nationality III. Applicant Residence, Residence (Office) Representative Name First Name Canada P. McDell, 1QQ4, Zhongmen Road, Mississauga, Ontario, Canada

Claims (1)

548271 Patent Application No. 086118465 Chinese Patent Application Replacement (June 1992) Chinese ^ Fan ^ Wai 丨 Public A8 BB C8 D8 Modified in this β supplement 1. A compound of formula (I), and isomers, A ... a pharmaceutically acceptable salt of a compound of formula (I) and its ⑴ I R-R1 is selected from (i) hydrogen; (Π) a branched or straight-chain CVC6 alkyl group; (iii) a Ci-C6 alkenyl group; (iv) (: 3-(: 8cycloalkyl group; (V) c4-c8cycloalkyl group, wherein The group is Cl_C2 and the cycloalkyl group is C 3 -C 6 soil pit group, (Vi) phenyl and i or 2 are independently selected from chlorine 'C Hs,-(CH2) pCF3 (where P is 0, 1 Or 2) and a phenyl group substituted with a substituent of a dentin; (vii) &lt; CH2) 2 Or one H; CH2) 2 —N (viii) (Ci-Cz alkyl) -phenyl 5 wherein the phenyl may be unsubstituted or independently selected from 1 or 2 independently selected from hydrogen 'CH3,-(CH2) pCF3 (p is O: \ 50 \ 50348.920613 DOC \ 5 \ LAN 丨 丨 ·, Μ I ---------------丨 丨 .......... 1 I, ...,-book size Applicable to China National Standard (CNS) A4 Regulation (210 X 297 mm) 548271 8 8 8 8 A BCD Application Patent Scope 1 or 2) and Substitutes for Substituting Substances; and IX 〇 18 R _Rie wherein Ri9 is independently and independently hydrogen, Cl-C6 alkyl or C C6 fluorenyl; A is selected from Wherein R8 and R9 are alkyl groups independently and independently; (ϋ) ΎΝχ ^ where R12 is selected from 11 and (: 1- € 6 alkyl, and the rule 13 is &lt; ^-(: 6 alkoxy); 111 qX〇c where Q is a saturated 5- or 6-membered heterocyclic ring with 5 or 6 selected from 2-O: \ 50 \ 50348-920613 DOC \ 5XLAN This paper size applies to China National Standard (CNS) A4 specifications (210 x 297 mm) 548271 A8 B8 C8 D8 VI. Patent application scope! SC, N and 0 atoms; B is selected from (i) phenyl and 1 or 2 independently selected from hydrogen, CH3, halogen, CF 3, C!-C 6 alkoxy, phenyl substituted with a light-weight 'nitro'amino' C! -C 6 alkylsulfide; (ϋ) CH3 (iii) naphthalene, acetone, benzo T7 sulfan, p-queline, p-phene. 2 · The compound of formula (I) according to item 1 of the scope of the patent application, wherein Q is selected from the group consisting of morphine, hexahydrogen P-bide and p-bidet; , C3-c5 cycloalkyl; and B is selected from phenyl, fluorenyl, indolyl, benzofuranyl, and quinolinyl. 3. The compound of formula (I) according to item 2 of the scope of patent application, wherein A is R8 and R9 are both ethyl; R1 is selected from hydrogen, methyl, ethyl, -CH2CH = CH2, -CH2-cyclopropane-3 O: \ 50 \ 50348-920613 D0C \ 5 \ LAN This paper is applicable to the standard Chinese National Standard (CNS) A4 specification (210 X 297 mm) 548271 A8 B8 C8 D8 6. Patent application scope, -CH2-phenyl; B is selected from phenyl, fluorenyl, indolyl, benzofuran Quinolinyl. 4. The compound of formula (I) according to item 1 of the scope of patent application, which is any one of the following: This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 548271 A8 B8 C8 D8 This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 0: · .5ϋ \ 5ΰ348-92ϋ613 DOC \ 5 \ L.AN '6 548271 A8 B8 C8 D8 VI. Scope of patent application This paper applies Chinese National Standard (CNS) A4 (210 x 297 mm) 548271 A8 B8 C8 D8 Patent Application Scope O: \ 50 \ 5034S-920613 DOC \ 5 \ LAN This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 548271 A8 B8 C8 D8 O: \ 50 \ 50348-920613 DOC \ 5VLAN This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 548271 8 8 8 8 A B c D 6. Scope of patent application 〇 N E Η〇 N ^ 2 B Η 9 O: \ 50 \ 50348-920613 DOC \ 5 \ LAN This paper size is applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 548271 A8 B8 C8 D8 This paper size applies to China National Standard (CNS) A4 specifications (210 &gt; &lt; 297 mm) 548271 8 8 8 8 A B c D, scope of patent application 548271 6. Scope of patent application 8 8 8 8 A B CD 〇Ϊ ^ Hno 〇 〇Λ50 \ 50348-920613 DOC \ 5 \ LAN 12- This absolute scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 548271 A8 B8 C8 D8 6. Scope of patent application O: \ 50 \ 50348-920613 DOC \ 5 \ LAN 13 This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 548271 A8 B8 C8 D8 — 1 _ Application scope • The compound of formula (I) according to any one of the claims 1 to 4 in the form of its hydrochloride, sulfate, tartrate or citrate. 6. The compound of formula (I) according to any one of claims 1 to 4 of the scope of patent application, which is for use in the treatment of pain. ^ 7. The compound of formula (I) according to item 6 of the scope of patent application, wherein the treatment is pain treatment. '8. The compound of formula (I) according to item 6 of the scope of the patent application, wherein the treatment is for spinal cord injury. 9. The compound of formula (1) according to item 丨 of the scope of patent application, which is used for manufacturing a medicament for treating pain. 10. The compound of formula (j) according to item 1 of the scope of patent application, which is used for the manufacture of a medicament for treating spinal cord injury. 11 · The compound of formula (I) according to item 1 of the scope of the patent application, which is used to diagnose the degradation or function of the opioid receptor in which the typical disease is present or involved. O: \ 50 \ 50348-920613 D〇C \ 5 \ L ^ N-1 4-「— *「 _, ΤΜίΠΊΐι ι, ιιιιιιι ^^ &quot;! m .fTLMdTCTgsrfuT—! _ ”... (C; NS) A4 size (210 x 297 mm) 548271 Diagnostic agent for incomplete disease state. 12. A diagnostic composition for diagnosing a degenerative or instable disease state in which a cymbal-like receptor of the typical disease is present or involved, which comprises a compound of formula (1) as claimed in item 1 of the patentable scope. &quot; 13.-: A pharmaceutical composition for treating pain, which contains the compound of formula (I) as the active ingredient in the first patent application range, and a pharmacologically and pharmaceutically acceptable carrier. 14. A method for preparing a compound of formula (1) in item i of the scope of patent application, which consists of a) ketone of formula (I) X NIR where R is as in formula (1) in item 1 of the scope of patent application And χ is the free radical 'reacting with the organometallic reagent of formula (j) or (k) 0) or 8. Μ (k) where A and B are as in formula (1) in item 1 of the scope of the patent application And M is a metal base; 〇: \: 50 \ 50348-920613 D0C \ ^ 15- lattice (210 ^ 97 公 董 ί 2 8 54 Compound wherein the reaction is performed in the presence or absence of a solvent to obtain formula (^) V6 \ ^ / (h N1R where A, B and R1 are as defined in formula (ι) in item i of the patent application range, and wherein R1 may also be a third butoxycarbonyl group; b) dehydrating the compound of formula (h) To obtain a compound of formula (1) in the scope of application for item i. 15 · —A compound of formula (h), A B 0H (h) N I Boc where A and B are as defined by formula (1) in item 1 of the scope of patent application. 16. · A compound of formula (h) according to step a) of item 4 of the scope of the patent application where O: \ 50 \ 50348-920613 DOC \ 5 \ LAN -16- '... ......... This standard is applicable to China National Standard (CNS) A4 specifications (210 &gt; &lt; 297 mm) 548271 A8 B8 C8 D8 Ch) R A is In the formula, R8 and R9 are both ethyl. 17. The compound according to item 16 of the scope of patent application, which is any of the following 2N E 2N t E 7 This nitrogen scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 548271 Patent application scope 〇 Ci 8 8 8 8 A B c D Et # Et ^ Ο F and O: \ 50 \ 50348-920613 DOO 5 \ LAN 18- L __ „_______ This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 548271 A8 B8 C8 D8 6. Scope of patent application -19- O: \ 50 \ 50348-920613 DOC \ 5 \ LAN This paper size applies to China National Standard (CNS) A4 (210X297 mm)